System and method for noninvasive analysis of subcutaneous tissue

ABSTRACT

Systems, devices and methods for noninvasive analysis of tissue, by irradiating a surface of the tissue with infrared radiation such that an interaction of the radiation with a component of the tissue other than water in two spectral bands is substantially identical, measuring an intensity of the radiation that emerges from the tissue in each of the spectral bands, determining change in at least one of shape and intensity of signals received by the at least one radiation detector, calculating a relative absorption by the tissue of radiation in one of the first and second spectral bands relative to absorption by the tissue of radiation in the other of the first and second spectral bands, and determining concentration of a predetermined substance, in accordance with the calculated relative absorption and in accordance with determined change in the received signal.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of application Ser. No.15/627,470, filed Jun. 20, 2017, which is a continuation-in-part ofapplication Ser. No. 14/465,311, filed Aug. 21, 2014, both of which areincorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to noninvasive analysis. Moreparticularly, the present invention relates to a system and method fornoninvasive analysis of subcutaneous tissue for determination ofsubstance concentration in the blood stream and/or in other subcutaneoustissue.

BACKGROUND OF THE INVENTION

Various medical conditions are characterized by accumulation of liquidsunder or behind the skin surface. Such conditions may include otitismedia, pressure ulcers, or other types of deep tissue injury underintact skin.

Medications or other substances may be introduced or delivered into thebloodstream. For example, a substance may be delivered orally to apatient, or may be injected into tissue or via an intravenous infusion.In some cases, it is important to monitor the concentration or amount ofthe substance in a patient's blood or tissue. Monitoring theconcentration or the amount may include drawing a blood or tissue samplefrom the patient.

In order to provide respiratory and cardiovascular support for patientsundergoing medical procedures, as well as monitoring the vital signs ofthe patient, anesthesiologists need to properly monitor the anesthetics.The degree of anesthesia reflects the degree of blockade of sensory,reflex, mental, and/or motor functions, which can be achieved by usinginhalational agents and/or intravenous anesthetics. Current methodscannot provide precise determination of the degree of anesthesia and/orthe concentration of anesthetic agents in the blood stream and/orprecisely determine the drug quantity required to provide a sufficient“degree of anesthesia”.

Propofol is a short-acting intravenously administered anesthetic that ismost commonly used for induction and maintenance of general anesthesiaand for procedural sedation. For example, it can be used in a regimenthat provides hypnosis, analgesia and muscle relaxation. Propofol isusually administered as a constant intravenous infusion in order todeliver and maintain a specific plasma concentration. It is thereforedesirable to evaluate plasma concentrations in real time to accuratelymaintain anesthetic efficacy. Currently there is no clinically usefulmethod for measuring blood Propofol concentrations on line and in realtime.

SUMMARY OF THE INVENTION

There is thus provided, in accordance with some embodiments of thepresent invention, a method for noninvasive analysis of tissue, themethod including: irradiating a surface of the tissue with short waveinfrared (SWIR) radiation in a first spectral band that is stronglyabsorbed by water, and with SWIR radiation in a second spectral bandsuch that an interaction of the radiation in both spectral bands with acomponent of the tissue other than water is substantially identical;measuring an intensity of the radiation that emerges from the tissue ineach of the spectral bands; calculating a relative absorption by thetissue of radiation in one of spectral bands relative to absorption bythe tissue of radiation in the other of the spectral bands; anddetermining a state of the tissue in accordance with the calculatedrelative absorption.

Furthermore, in accordance with some embodiments of the presentinvention, the first spectral band is in the wavelength range of 1400 nmto 1500 nm.

Furthermore, in accordance with some embodiments of the presentinvention, the second spectral band is in the wavelength range of 1000nm to 1350 nm or 1500 nm to 2100 nm.

Furthermore, in accordance with some embodiments of the presentinvention, a gap in wavelength between the first and second spectralbands is less than 200 nm.

Furthermore, in accordance with some embodiments of the presentinvention, measuring the intensity includes measuring the intensity ofthe radiation that is transmitted across the tissue (e.g., passingthrough the tissue and not reflected back towards the radiation source).

Furthermore, in accordance with some embodiments of the presentinvention, the tissue includes tissue of a finger or an ear.

Furthermore, in accordance with some embodiments of the presentinvention, measuring the intensity includes measuring the intensity ofthe radiation that is reflected by the tissue.

Furthermore, in accordance with some embodiments of the presentinvention, measuring the intensity includes measuring the intensity ofthe radiation that emerges from the tissue at a plurality of lateraldistances from a location of the irradiating of the tissue.

Furthermore, in accordance with some embodiments of the presentinvention, the state of the tissue includes a concentration of asubstance in blood.

Furthermore, in accordance with some embodiments of the presentinvention, the substance is an introduced substance.

There is further provided, in accordance with some embodiments of thepresent invention, a system for noninvasive analysis of tissue, thesystem including: at least one source of infrared radiation to irradiatethe tissue, the infrared radiation including SWIR radiation in a firstspectral band that is strongly absorbed by water, and includingradiation in a second spectral band such that an interaction of theradiation in both spectral bands with a component of the tissue otherthan water is substantially identical; at least one radiation detectorto measure an intensity of radiation in each of the two spectral bandsthat emerges from the tissue (e.g., reflected from the tissue or passingthrough the tissue, to come out at another side), and a processor thatis configured to calculate a relative absorption by the tissue ofradiation in one of spectral bands relative to absorption by the tissueof radiation in the other of the spectral bands and determine a state ofthe tissue in accordance with the calculated relative absorption.

Furthermore, in accordance with some embodiments of the presentinvention, wherein the at least one radiation detector is configured tomeasure the intensity of the radiation that emerges from a surface ofthe tissue that is irradiated by the at least one radiation source.

Furthermore, in accordance with some embodiments of the presentinvention, the at least one radiation detector is configured to measurethe intensity of the radiation that emerges from the surface of thetissue at a plurality of lateral distances from the at least oneradiation source.

Furthermore, in accordance with some embodiments of the presentinvention, the at least one radiation detector includes a plurality ofradiation detectors separated by different lateral distances from the atleast one radiation source.

Furthermore, in accordance with some embodiments of the presentinvention, the at least one radiation detector is configured to measurethe radiation that emerges from a surface of the tissue that issubstantially opposite a surface of the tissue that is irradiated by theat least one radiation source.

Furthermore, in accordance with some embodiments of the presentinvention, the system includes a removable cover for placement over anaperture of the at least one radiation source or of the at least oneradiation detector.

Furthermore, in accordance with some embodiments of the presentinvention, the at least one radiation source includes two radiationsources, one of the sources being configured to emit radiation in thefirst spectral band and the other being configured to emit radiation inthe second spectral band.

Furthermore, in accordance with some embodiments of the presentinvention, the at least one radiation detector includes two radiationdetectors, one of the detectors being configured to measure an intensityof radiation in the first spectral band and the other being configuredto measure an intensity of radiation in the second spectral band.

Furthermore, in accordance with some embodiments of the presentinvention, the system includes a dispersive element to separate spectralcomponents of the infrared radiation and a micro-mirror array, themicro-mirror array being operable to direct a selected spectralcomponent of the infrared radiation to the tissue or to the at least oneradiation detector.

Furthermore, in accordance with some embodiments of the presentinvention, the first spectral band is in the wavelength range of 1400 nmto 1500 nm.

Furthermore, in accordance with some embodiments of the presentinvention, the second spectral band is in the wavelength range of 1000nm to 1350 nm or 1500 nm to 2100 nm.

There is further provided, in accordance with some embodiments of thepresent invention, a method for determining a state of tissue, themethod including: irradiating a surface of the tissue with SWIRradiation in a first spectral band in the wavelength range 1300 nm to1430 nm, and with SWIR radiation in a second spectral band such that aninteraction of the radiation in both spectral bands with a component ofthe tissue other than water is substantially identical; measuring anintensity of the radiation that emerges from the tissue in each of thespectral bands; and calculating an absorption by the tissue of radiationin the two spectral bands, the absorption being indicative of the stateof the tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

In order for the present invention to be better understood and for itspractical applications to be appreciated, the following Figures areprovided and referenced hereafter. It should be noted that the Figuresare given as examples only and in no way limit the scope of theinvention. Like components are denoted by like reference numerals.

FIG. 1A is a schematic drawing of a system for noninvasive analysis ofsubcutaneous liquids based on reflection of infrared radiation, inaccordance with an embodiment of the present invention.

FIG. 1B is a schematic illustration of a plurality of componentapertures of an optical head of the system shown in FIG. 1A.

FIG. 2A is a schematic drawing of a measurement unit of a system fornoninvasive analysis of subcutaneous liquids based on transmission ofinfrared radiation, in accordance with an embodiment of the presentinvention.

FIG. 2B schematically illustrates attachment of the measurement unit ofFIG. 2A to a finger.

FIG. 2C schematically illustrates attachment of the measurement unit ofFIG. 2A to an ear.

FIG. 3 shows an example of a graph of spectral reflectance.

FIG. 4 shows a graph of an example of a relationship of absorbance toconcentration of a substance.

FIG. 5 is a flowchart depicting a method for noninvasive analysis ofsubcutaneous liquids, in accordance with an embodiment of the presentinvention.

FIG. 6A schematically illustrates a system for measurement of reflectionat a distance from a radiation source, in accordance with an embodimentof the present invention.

FIG. 6B schematically illustrates an arrangement of a measurement headfor concurrent measurement of radiation that emerges from a surface atdifferent lateral distances from the radiation source, in accordancewith an embodiment of the present invention.

FIG. 7 schematically illustrates paths of incident radiation todifferent detector locations, in accordance with an embodiment of thepresent invention.

FIG. 8 is a block diagram showing elements of a measurement unit, inaccordance with an embodiment of the present invention.

FIG. 9 shows an example graph of detection of injected substance overtime, in accordance with an embodiment of the present invention.

FIG. 10 shows an example of a transmission measurement unit, inaccordance with an embodiment of the present invention.

FIG. 11A shows a top view of a reflectance measurement unit, inaccordance with an embodiment of the present invention.

FIG. 11B shows a side view of the reflectance measurement unit, inaccordance with an embodiment of the present invention.

FIG. 11C shows a cross-section perspective view of the reflectancemeasurement unit, in accordance with an embodiment of the presentinvention.

FIG. 12A shows a portion of flowchart for a method of noninvasiveanalysis of tissue, in accordance with an embodiment of the presentinvention.

FIG. 12B shows the second portion of the flowchart of FIG. 12A, inaccordance with an embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

In the following detailed description, numerous specific details are setforth in order to provide a thorough understanding of the invention.However, it will be understood by those of ordinary skill in the artthat the invention may be practiced without these specific details. Inother instances, well-known methods, procedures, components, modules,units and/or circuits have not been described in detail so as not toobscure the invention.

Although embodiments of the invention are not limited in this regard,discussions utilizing terms such as, for example, “processing,”“computing,” “calculating,” “determining,” “establishing”, “analyzing”,“checking”, or the like, may refer to operation(s) and/or process(es) ofa computer, a computing platform, a computing system, or otherelectronic computing device, that manipulates and/or transforms datarepresented as physical (e.g., electronic) quantities within thecomputer's registers and/or memories into other data similarlyrepresented as physical quantities within the computer's registersand/or memories or other information non-transitory storage medium(e.g., a memory) that may store instructions to perform operationsand/or processes. Although embodiments of the invention are not limitedin this regard, the terms “plurality” and “a plurality” as used hereinmay include, for example, “multiple” or “two or more”. The terms“plurality” or “a plurality” may be used throughout the specification todescribe two or more components, devices, elements, units, parameters,or the like. Unless explicitly stated, the method embodiments describedherein are not constrained to a particular order or sequence.Additionally, some of the described method embodiments or elementsthereof can occur or be performed simultaneously, at the same point intime, or concurrently. Unless otherwise indicated, us of the conjunction“or” as used herein is to be understood as inclusive (any or all of thestated options).

Some embodiments of the invention may include an article such as acomputer or processor readable medium, or a computer or processornon-transitory storage medium, such as for example a memory, a diskdrive, or a USB flash memory, encoding, including or storinginstructions, e.g., computer-executable instructions, which whenexecuted by a processor or controller, carry out methods disclosedherein.

In accordance with an embodiment of the present invention, reflection ofradiation or transmission of radiation by tissue in a region of the bodyis measured. In some embodiments, reflected radiation may refer toradiation that emerges from the tissue via a surface through which thetissue was irradiated or illuminated. Thus, reflected radiation mayresult from one or more of radiation that is reflected from an interfacebetween dissimilar media and radiation that is scattered in the backwarddirection. For example, a measurement unit may be placed on or near asurface of the tissue, e.g., a skin surface of the patient's body withsuperficial blood vessels, on oral mucosa of inner lip, an eardrum, oranother surface. The measurement unit may include one or more radiationsources and one or more radiation detectors. The measurement unit may beconfigured to measure reflection. For example, the radiation sources maybe configured to irradiate or illuminate a tissue surface (e.g., a skinsurface of a patient). When irradiating the tissue surface, theradiation penetrates into the tissue. The radiation detectors may beaimed at the irradiated surface so as to detect radiation that isreflected or backscattered by the tissue that is covered by the surface.In other cases, the radiation sources and detectors may be configured tomeasure transmission of the radiation through the tissue. For example,measurement unit may be configured such that radiation that is emittedby the radiation sources is directed toward the radiation detectors.Thus, when tissue (e.g., a part of the patient's body such as an ear,finger, toe, fold of skin, or other part of the body) is placed in theoptical path from the radiation source to the corresponding radiationdetector, transmission of the radiation through the tissue may bemeasured.

The reflection or transmission measurement may be indicative of a stateof the tissue. The tissue may include subcutaneous liquids such as bloodor other fluids. In some embodiments, the term “subcutaneous”, may referto a depth within tissue, which may or may not be covered with skin. Forexample, subcutaneous liquid may be within or behind a membrane, such aswithin or behind the eardrum, or within lung tissue and/or such as oralmucosa of inner lips or within superficial blood vessel. The state ofthe tissue may be indicative of a medical condition in the patient. Forexample, a medical condition may include otitis media, early stages ofpressure ulcers, or other types of deep tissue injury under intact skinin which liquids accumulate subcutaneously. A state of the tissue mayinclude a concentration of a substance in the blood or othersubcutaneous fluids. The substance (e.g., a medication, contrast agent,food component or supplement, or other administered product) may havebeen administered to the patient (e.g., orally, or via injection orinfusion), may be a product of physiological processes on anadministered substance, or may be produced by the patient's body. Forexample, the most common pressure ulcers are above the heel bone underthe skin. The heel bone is covered with a thin fatty layer which isnormally composed of triglycerides. When ischemia starts thetriglycerides fatty tissue decomposes into glycerol and free fattyacids. According to some embodiments, a lookup table containingdifferent concentrations of, for example, glycerol and free fatty acidsmay be created, and may further include data regarding such substancesabsorption (e.g., in different wavelengths). A processor, may determinestate of the tissue above the heel bone (or at any other location) bycomparing the optical readings from the examined tissue, to theabsorption values in the lookup table, and based on the determinedconcentration of the different substances, determine the existence anddegree or severity of DTI.

The reflection or transmission is measured in at least two spectralbands of the visible (VIS) and/or near infrared (NIR) and/or shortwaveinfrared (SWIR) spectral region of the electromagnetic spectrum. As usedherein, the SWIR spectral region is used to include the wavelength rangeof about (e.g., ±10%) 1000 nm to about 2500 nm. The shorter wavelengthsof this spectral region are sometimes referred to as near infrared(NIR). It should be noted that as used herein, the VIS-NIR-SWIR spectralregion may include the wavelengths range of ˜350 nanometers (nm) to˜2500 nm, and MIR may include the wavelengths range of ˜2500 nm to 15000nm waveband.

A first spectral band may be in a portion of the SWIR spectral regionwhere radiation is strongly, or more strongly, absorbed by water (e.g.,in the wavelength band from about 1400 nm to about 1500 nm) as comparedto adjacent or other bands. As used herein, radiation is considered toby strongly absorbed when absorption (e.g., as characterized by anabsorption coefficient) is at least an order of magnitude (approximately10 times or more) greater than in the comparison band.

A second spectral band is in an adjacent SWIR spectral band, e.g., inthe wavelength band from about 1000 nm to about 1350 nm, or in thewavelength band from about 1500 nm to about 2100 nm. The second spectralband is sufficiently close to the first spectral band such that aninteraction of radiation in both spectral bands (e.g., absorption orscattering) with tissue components other than water is substantiallyidentical (e.g., having the same or very similar behavior interactionwith the tissue). In some embodiments, substantially identical may referto measurements at two wavebands for the change of measuredbackscattered power over sampling time with the change of 3 dB and/orthe mean intensity “I” (or mean square of intensity) of √2<I>. In someembodiments, substantially identical may refer to measurements at twowavebands with a similarity test (e.g., t-test, Kruskal-Wallis test,etc.) with the p-value being above 0.05. In some embodiments,substantially identical may refer to measurements at two wavebands whileassuming that for a given waveband all chromophores other than water mayabsorb and scatter the radiation in the same way, for instance thephoton-tissue interaction may be constant for a given waveband. Forexample, absorption of radiation in the spectral band of about 1000 nmto about 1800 nm by such tissue components other than water such ashemoglobin, melanin, and other chromophores is approximately constant(with absorption coefficients in the range of about 0.1 cm⁻¹ to about 1cm⁻¹). The scattering coefficient is about 5 cm⁻¹ to about 15 cm⁻¹.Thus, radiation may penetrate as deep as 8 cm to 10 cm into tissue.

For example, a gap between the two bands may be no more than 200 nm. Insome cases, the gap between the two bands may be no more than 100 nm.

For example, two or more of the radiation sources may be configured toemit radiation in different spectral bands of the SWIR spectral region.As another example, two or more of the radiation detectors may beconfigured to detect different radiation in different spectral bands ofthe SWIR spectral region and/or the visible spectral region (alsoreferred to as VIS). Both the radiation sources and the radiationdetectors may be limited to particular spectral bands.

For example, the source or detector may include a wavelength selectionarrangement that incorporates a spectrally dispersive element (e.g., agrating, prism, or spectrally selective optical coating), focusingoptics (e.g., lenses or mirrors), and a micro-mirror array that containsindividually rotatable micro-mirrors (or rotatable in groups). Radiationoriginating from the radiation source (for irradiating the tissue) orfrom the tissue (e.g., after reflection or transmission) may be focusedonto the dispersive element to spatially separate different spectralcomponents (e.g., wavelength ranges or spectral bands) of the radiation.For example, different wavelengths of the radiation may be directed indifferent directions. Spectrally separated radiation from the dispersiveelement may be focused onto the micro-mirror array. For example, eachspectral component may be incident on a different micro-mirror of thearray. Therefore, each micro-mirror may be selectively rotated to directa particular spectral component of the radiation either toward or awayfrom a source aperture (to irradiate the tissue surface) or a detector(to be detected as transmitted or reflected radiation).

In some cases, either the spectral bands in which radiation is emittedby different radiation sources, or the spectral bands to which differentradiation detectors are sensitive, may partially or completely overlap.In such a case, spectral separation may be effected by another of thecomponents (e.g., source, detector, or optics).

In biological tissue, the absorption of radiation in a particularspectral band (e.g., in the SWIR range) may be determined thecontributions of various substances or chromophores that absorbelectromagnetic radiation of different wavelengths. Chromophores arefunctional groups of molecules that absorb light or electromagneticradiation to various extents in a spectral band. Each chromophore ischaracterized by a particular characteristic absorption as a function ofwavelength, and which may be used to identify the presence of thatmolecule.

In practice, only a few chromophores contribute to the absorption in theNIR-SWIR range from about 800 nm to about 2400 nm. In this region, majorcontributions to absorption in the body arise from the presence of (oxy-or deoxy-) hemoglobin, water, and fat and melanin. Other chromophoresthat may potentially contribute slightly (e.g., about 1%-3%) to theabsorption include myoglobin, cytochrome, bilirubin, lipids and othersubstances.

In SWIR radiation with wavelength greater than about 1000 nm, thecontribution of water to absorption is greater than that of hemoglobin,melanin and other chromophores.

For example, one of the spectral bands may include the SWIR band fromabout 1400 nm to about 1500 nm, which is strongly absorbed by water.Another of the spectral bands may include the SWIR band from about 1000nm to about 1350 nm, or the SWIR band from about 1500 nm to about 2100nm. Radiation in the spectral region from about 1350 nm to 1400 nm,where the absorption by water rapidly changes with wavelength (with alarge slope in a curve of absorption versus wavelength), may not be usedin some cases

In some cases, a rate of change of absorption of radiation as a functionof the wavelength may be measured in the spectral region from about 1300nm to about 1430 nm. In this spectral region, the absorption by waterrapidly changes with wavelength. The high rate of change of absorptionwith wavelength (absolute rate of change for absorption in 1 mm of waterbeing greater than 0.007 nm⁻¹) may be exploited to detect the presenceof water (or an amount or concentration of water) in the tissue. Forexample, a slope of a graph of absorption (or reflection ortransmission) versus wavelength may be calculated. As an example, it maybe noted that in FIG. 3, the slopes of normal tissue curve 72 and ofdisease tissue curve 74 (having different water content) noticeablydiffer from one another in the spectral range of 1300 nm to 1430 nm.

The measurement of the reflection or transmission may be performed in atleast two different but adjacent spectral bands of the SWIR region ofthe electromagnetic spectrum. The results of the reflection ortransmission measurement may be analyzed by comparison with previouslymeasured or calibrated results. The comparison may be utilized todetermine the state of the subcutaneous tissue.

For example, one of the spectral bands may be selected such that thereflection or transmission in that band is relatively unaffected by thepresence or absence of the medical condition. The measured reflection ortransmission in this spectral band may serve as a reference. Forexample, the reference measurement may set a baseline value or temporarycalibration for measurements in the presence of conditions that arespecific to the measurement. The conditions may be related to thepatient's body (e.g., dimensions or other properties of a skin or tissuesurface or body part on which the measurements are made). The conditionsmay be related to drift or transient variation in properties of themeasurement unit that is used to perform the reflection or transmissionmeasurements.

Measurements may be further calibrated by monitoring a dark signal(e.g., when a radiation detector is shielded from radiation) and anintensity of the radiation source (e.g., by providing a direct channelof radiation from the radiation source to the corresponding radiationdetector).

Another of the spectral bands may be selected such that a reflection ortransmission measurement in that band is sensitive to the state of thetissue. Thus, when adjusted in accordance with the various reference andcalibration measurements, the measurement in that other spectral brandmay be indicative of the state of the tissue. Thus, the state of thetissue may be detected noninvasively.

For example, one of the spectral bands may include wavelengths of SWIRelectromagnetic radiation that are strongly (e.g., almost completely)absorbed by water. Another of the spectral bands may include SWIRelectromagnetic radiation that is largely transmitted by water. In somecases, one of the spectral bands may include SWIR electromagneticradiation whose absorption varies rapidly with wavelength (e.g., insteadof, or in addition to, the spectral band in which radiation is stronglyabsorbed).

FIG. 1A is a schematic drawing of a system for noninvasive analysis ofsubcutaneous liquids based on reflection of infrared radiation, inaccordance with an embodiment of the present invention.

Liquid analysis system 10 includes reflection measurement unit 12.Reflection measurement unit 12 includes infrared radiation source 14 andradiation (e.g., infrared) detector 16. Unit aperture 19 on optical head13 of reflection measurement unit 12 is configured to be placed on ornear a tissue surface 22 of a patient so as to measure infraredradiation that is reflected from tissue that is covered by tissuesurface 22. Liquid analysis system 10 is configured to determine thestate of subcutaneous tissue, such as the presence of absence of asubcutaneous medical condition in tissue that is covered by tissuesurface 22, or to measure the presence or absence of an administeredsubstance in blood that flows via the tissue.

Reflection measurement unit 12 may be configured to be held andmanipulated by a single hand of a user. For example, the user mayinclude a healthcare professional, a caregiver, or the patient.Reflection measurement unit 12 may include an internal power source inthe form of a battery or other self-contained power source, or may beconnectable to an external power source. Reflection measurement unit 12,optical head 13, or both may have a generally or substantiallycylindrical form, or may have another geometrical form or shape. Unitaperture 19 may thus have a substantially round or elliptic shape, oranother shape.

Unit aperture 19 of optical head 13 may include one or more componentapertures.

FIG. 1B is a schematic illustration of a plurality of componentapertures of an optical head of the system shown in FIG. 1A. Unitaperture 19 includes a plurality of component apertures 40. Eachcomponent apertures 40 may be configured to enable passage of radiationfrom a single component infrared source of infrared radiation source 14or to a component detector of radiation (e.g., infrared) detector 16. Inthe configuration shown, unit aperture 19 is round and componentapertures 40 are arranged in a hexagonal pattern. Other configurationsmay include other shapes of unit aperture 19 or other arrangements ofcomponent apertures 40.

Infrared radiation source 14 is configured to irradiate tissue surface22 with SWIR radiation via unit aperture 19 of optical head 13. Infraredradiation source 14 may include one or more separate component infraredsources. For example, two or more component infrared sources may eachproduce SWIR radiation in one or more spectral bands. For example,infrared radiation source 14 may include tungsten-halogen or otherincandescent lamp, a xenon lamp or other gas emission radiation source,a fluorescent radiation source, an electronic radiation source (e.g.,light emitting diode, laser diode, or laser), or other radiation source.

Infrared radiation source 14 may include a single wideband infraredsource that emits radiation over two or more spectral bands. In somecases, infrared radiation from a single wideband infrared source may beseparately channeled via separate spectral band selection devices (e.g.,that include filters, prisms, or gratings) to form effective single-bandsources. For example, the separate channeling may be performedsequentially to radiate infrared radiation in different spectral bandsin quick succession (e.g., less than a millisecond) via a singlecomponent aperture 40 of unit aperture 19. As another example, theradiation from the wideband source may be divided (e.g., using a beamsplitter) and concurrently channeled via different band-selectiondevices to concurrently radiate in different spectral bands via separatecomponent apertures 40 of unit aperture 19.

Optics 18 of optical head 13 may direct infrared radiation from infraredradiation source 14 out unit aperture 19 (or from a component infraredsource of infrared radiation source 14 out a component aperture 40 ofunit aperture 19) to tissue surface 22. For example, optics 18 mayinclude one or more mirrors, reflectors, light pipes or optical fibers,lenses, filters, gratings, polarizers, beam splitters, prisms,apertures, collimators, shutters, or other components. Similarly, optics18 may direct radiation from tissue surface 22 (e.g., reflectedradiation) via unit aperture 19 to infrared radiation detector 16 (orvia a component aperture 40 of unit aperture 19 to a component detectorof infrared radiation detector 16). One or more components of optics 18may function both to direct radiation from infrared radiation source 14to tissue surface 22, and to direct radiation from tissue surface 22 toinfrared radiation detector 16. Alternatively or in addition, separatecomponents of optics 18 may be provided for either directing radiationfrom infrared radiation source 14 to tissue surface 22 or for directingradiation from tissue surface 22 to infrared detector 16.

Optics 18 may be or may include a dispersive element (e.g., grating,prism, element with spectrally selective optical layers or coating, oranother dispersive element), and a micro-mirror array for directingradiation of one or more selected wavelengths toward unit aperture 19(e.g., for limiting irradiation of tissue surface 22 to selectedwavelengths), or toward infrared detector 16 (e.g., for limitingdetection of reflected or transmitted radiation to selectedwavelengths).

Optics 18 may be configured to direct a portion of radiation that isemitted by infrared radiation source 14 to infrared detector 16. Thus,an intensity of the radiation that is emitted by infrared radiationsource 14 may be monitored. Optics 18 may include a shutter or othercomponent that is configured to block radiation (e.g., that is emittedby infrared radiation source 14) from reaching infrared detector 16.When the radiation is blocked, a baseline measurement may be made (e.g.,a dark current or a detection level that is due to stray radiation).

Infrared detector 16 may be configured to detect SWIR radiation fromtissue surface 22 that enters reflection measurement unit 12 via unitaperture 19. Infrared detector 16 may include one or more componentdetectors. For example, radiation that is reflected by tissue surface 22may be enabled to impinge on a component detector of infrared detector16 via one of component apertures 40.

Two or more different component radiation detectors may be configured todetect, or be optimized to detect, SWIR radiation in one or morespectral bands. A component detector may include a solid state or otherphotoelectric transducer or photodetector that is configured oroptimized for one or more spectral bands of SWIR radiation. A componentdetector may include a thermal detector, a photon detector (e.g.,including InGaAs), or another type of wideband detector. The temperatureof a component detect of infrared detector 16 may be regulated (e.g.,via thermoelectric cooling or heating) or may be unregulated.

Infrared detector 16 or controller 28 may include an amplifier toamplify a detection signal that is produced by infrared detector 16. Forexample, the amplifier may include a trans-impedance amplifier or otheramplifier.

Infrared detector 16 or controller 28 may include a logarithmicconverter that enables direct calculation of an absorbance value of thetissue, or of a quantity that is proportional to an absorbance. Theabsorbance data may be used to analyze a liquid, such as water or blood,below tissue surface 22 (e.g., detect a pressure ulcer or aconcentration of a drug or other substance in the blood).

Component apertures 40 may be arranged such that radiation in aparticular wavelength band that is emitted by a particular componentinfrared source of infrared radiation source 14 and that is reflected bytissue surface 22 is likely to impinge on a corresponding (e.g.,configured or optimized to detect radiation in that same wavelengthband) component detector of infrared detector 16. For example, thepositions of a pair of corresponding component apertures 40 may bearranged such that radiation that irradiates tissue surface 22 via oneof the corresponding component apertures 40 may be specularly reflectedby tissue surface 22 into the other of the pair of correspondingcomponent apertures 40.

Unit aperture 19 of optical head 13 may be configured to be placedagainst or near tissue surface 22. Optical head 13 may be provided witha removable protective cover 20 that may be placed over unit aperture 19when reflection measurement unit 12 is in use. At least an outer surfaceof removable protective cover 20 may be constructed of materials thatare suitable (e.g., approved by an appropriate organization) for contactwith human skin or other tissue surfaces. At least a region ofprotective cover 20 (e.g., a region that is configured for placementover unit aperture 19) is substantially transparent or translucent inthe spectral bands in which reflection measurement unit 12 is configuredto operate. Suitable materials may include, for example, rigid vinyl,polycarbonate, POLY IR® plastic materials, or other materials such aspoly urethane (PU), thermoplastic elastomers (TPE), silicones (LSR) andthe like.

Removable protective cover 20 may include a structure (e.g., tab,projection, notch, clip, or other structure) that cooperates withcorresponding structure on optical head 13 to prevent or inhibitremovable protective cover 20 from accidentally or unintentionallyfalling off of optical head 13, e.g., during use.

Protective cover 20 may be disposable, cleanable, or sterilizable.Removable protective cover 20 may be removed from optical head 13 andreplaced (e.g., with a different removable protective cover 20, or withthe same removable protective cover 20 after cleaning and sterilization)between uses of reflection measurement unit 12 on different patients.Use of removable protective cover 20 may enable sanitary use ofreflection measurement unit 12 on different patients while not exposingreflection measurement unit 12 from repeated cleaning or sterilization.

Liquid analysis system 10 may include a controller 28. Controller 28 mayinclude a microcontroller unit (MCU), or one or more other types ofcontroller, microprocessor or processor. Controller 28 may include forexample two or more intercommunicating devices or units. Controller 28may be configured to control operation of infrared radiation source 14,and to receive signals that are indicative of detected radiation frominfrared detector 16. For example, controller 28 may include circuitrythat is configured to control operation of infrared radiation source 14and infrared detector 16. Controller 28 may be configured to operate inresponse to operation of user controls 27. For example, user controls 27may include one or more user touch-operable controls, such aspushbuttons, dials, switches, levers, touch-sensitive surfaces, or othertouch-operable controls. User controls 27 may include other types ofcontrols, such as light-sensitive controls, sound-operated controls,electromagnetically-operable controls, proximity sensors, pressuresensors, or other types of controls.

Controller 28 may be configured to dynamically adjust the intensity ofradiation that is emitted by infrared radiation source 14, e.g., inaccordance with intensities that are detected by infrared detector 16.For example, the intensity may be adjusted to accommodate various tissuethicknesses, skin coloration, or other characteristics. The intensitiesof a component infrared source may be adjusted in accordance with outputof another component infrared source.

Controller 28 may be configured to digitally filter the signals ofinfrared detector 16, e.g., to remove effects of baseline wandering andartifacts caused by patient movement.

Controller 28 may include a processor or processing units that may beconfigured to operate in accordance with programmed instructions.Controller 28 or a processor of controller 28 may communicate with anexternal device 30 via connection 36. External processing device 30 mayrepresent a device with processing capability, such as a computer,smartphone, or other device. External processing device 30 may beportable (e.g., a portable computer or smartphone) or may be fixed(e.g., a server). External processing device 30 may include orcommunicate with an input device 34 (e.g., keyboard, keypad, touchscreen, pointing device, or other input device), an output device 32(e.g., display screen or other output device), or both. Connection 36may represent a wire or cable connection, a wireless connection (e.g.,Bluetooth), a network connection, or another communications connection.

External processing device 30 may be utilized to communicate commands orprogrammed instructions to control operation of controller 28. Forexample, external processing device 30 may be operated using inputdevice 34 to download parameters or instructions (e.g., a measurementprotocol) to controller 28. Measured results from operation ofreflection measurement unit 12, or results of analysis of the measuredresults, preformed by, for example, external processing device'sprocessor 38, may be output by output device 32 of external processingdevice 30 for examination or review by a user of liquid analysis system10.

External processing device 30 may communicate (e.g., via a network suchas the Internet) with one or more other processors, computers, orservers. For example, measure spectral reflection or transmission datamay be communicated to a remote server. The remote server may analyzethe transmitted data and return a diagnosis or other indication of astate of a medical condition.

Controller 28 may communicate with memory 24 (and/or external processingdevice's memory 39). Memory 24 may include one or more volatile ornonvolatile memory devices. Memory 24 may be incorporated withinreflection measurement unit 12, external processing device 30, orelsewhere. Memory 24 may be utilized to store, for example, programmedinstructions for operation of controller 28, data or parameters for useby controller 28 during operation, or results of operation of controller28.

Controller 28 and or processor 38 may communicate with data storagedevice 26. Data storage device 26 may include one or more fixed orremovable nonvolatile data storage devices. Data storage device 26 maybe incorporated within reflection measurement unit 12, externalprocessing device 30, or elsewhere. For example, data storage device 26may include a computer readable medium for storing program instructionsfor operation of processing unit of controller 28 or of externalprocessing device 30. It is noted that data storage device 26 may beremote from the processing unit. In such cases data storage device 26may be a storage device of a remote server storing an installationpackage or packages that can be downloaded and installed for executionby the processing unit. Data storage device 26 may be utilized to storedata or parameters for use by controller 28 during operation or resultsof operation of controller 28 (e.g., detection of radiation).

Data storage device 26 may be used to store data that relates spectralabsorption, transmission, or reflection characteristics of tissuesurface 22 to one or more medical conditions. The data may be stored inthe form of a database. Processor or controller 28, or another processoror controller may be configured to carry out methods as describedherein.

In accordance with an embodiment of the present invention, a system fornoninvasive analysis of subcutaneous liquids may be based on measuredtransmission of SWIR radiation.

FIG. 2A is a schematic drawing of a measurement unit of a system fornoninvasive analysis of subcutaneous liquids based on transmission ofinfrared radiation, in accordance with an embodiment of the presentinvention.

Transmission measurement unit 50 may be used in a system for noninvasiveanalysis of subcutaneous liquids, such as in liquid analysis system 10(e.g., in place of, or in addition to, reflection measurement unit 12 ofFIG. 1A). Transmission measurement unit 50 is configured to measuretransmission through a body part 52. For example, body part 52 mayrepresent a part of the body (e.g., ear, finger, fold of skin) throughwhich a measurable fraction of SWIR radiation is transmitted.

Transmission measurement unit 50 includes radiation source arm 54 anddetection arm 55.

Radiation source arm 54 may include infrared radiation source 14 andsource optics 53 a. In some cases, infrared radiation source 14 may belocated outside of radiation source arm 54. In such a case, sourceoptics 53 a may be configured (e.g., with a mirror, light pipe, oroptical fiber) to convey radiation from infrared radiation source 14 tosource arm aperture 57 a.

As described above, infrared radiation source 14 may include two or moreseparate component infrared sources. Source optics 53 a may beconfigured to convey radiation from the component infrared sources,concurrently or sequentially, to source arm aperture 57 a, or toseparate component apertures of source arm aperture 57 a.

Source optics 53 a may be or may include a dispersive element (e.g.,grating, prism, element with spectrally selective optical layers orcoating, or another dispersive element), focusing optics, and amicro-mirror array for directing radiation of one or more selectedwavelengths of radiation from infrared radiation source 14 toward sourcearm aperture 57 a.

Detection arm 55 may include infrared detector 16 and detector optics 53b. In some cases, infrared detector 16 may be located outside ofdetection arm 55. In such a case, detector optics 53 b may be configured(e.g., with a mirror, light pipe, or optical fiber) to convey radiationfrom detection arm aperture 57 b to infrared detector 16.

As described above, infrared detector 16 may include two or moreseparate component detectors. Detector optics 53 b may be configured toconvey radiation from detection arm aperture 57 b, concurrently orsequentially, to component detectors of infrared detector 16, or fromseparate component apertures of detection arm aperture 57 b to componentdetectors of infrared radiation detector 16.

Detector optics 53 b may include a dispersive element (e.g., grating,prism, element with spectrally selective optical layers or coating, oranother dispersive element), focusing optics, and a micro-mirror arrayfor directing radiation of one or more selected wavelengths of radiationfrom detector arm aperture 57 b toward infrared detector 16.

Radiation source arm 54, detection arm 55, or both, may be rotatedoutward (away from one another) or inward (toward one another). Outwardrotation of radiation source arm 54 or detection arm 55 may enableinsertion of body part 52 between the arms. Inward rotation of radiationsource arm 54 or detection arm 55 may bring source arm aperture 57 a anddetection arm aperture 57 b into contact with or near to body part 52.Source arm aperture 57 a and detection arm aperture 57 b may each becovered with a removable protective cover 20.

A rotation mechanism 56 may be configured to enable the outward orinward rotation of radiation source arm 54 and detection arm 55. Forexample, rotation mechanism 56 may include a hinge, gimbal, bearing, orother mechanism to enable rotation of radiation source arm 54 ordetection arm 55. For example, a separate rotation mechanism 56 for oneof radiation source arm 54 and detection arm 55. Separate rotationmechanisms 56 may be provided for both radiation source arm 54 anddetection arm 55 (e.g., as shown schematically in FIG. 2A). A singlerotation mechanism 56 may be provided (e.g., a single hinge mechanism)between radiation source arm 54 and detection arm 55 (e.g., as shownschematically in FIGS. 2B and 2C). Rotation mechanism 56 may include aspring, latch, or other mechanism to hold radiation source arm 54 anddetection arm 55 against body part 52 when body part 52 is insertedbetween radiation source arm 54 and detection arm 55. Thus, rotationmechanism 56 may attach transmission measurement unit 50 to body part52.

Rotation mechanism 56 may be configured to enable measurement of athickness of body part 52. For example, rotation mechanism may includean encoder or other measuring device for measuring an angle of rotationof rotation mechanism 56. Alternatively or in addition, rotationmechanism may include an angular scale or mechanical rotation gauge fordetermining an angle of rotation of rotation mechanism 56. A measuredrotation angle, together with a known distance from (e.g., and axis ofrotation of) rotation mechanism 56 from source arm aperture 57 a or fromdetection arm aperture 57 b may be used (e.g., by a processor orcontroller) to calculate the thickness.

When source arm aperture 57 a and detection arm aperture 57 b arepositioned on or near body part 52, transmission measurement unit 50 maybe operated to measure of transmission of SWIR radiation from infraredradiation source 14 through body part 52 to infrared detector 16.

FIG. 2B schematically illustrates attachment of the measurement unit ofFIG. 2A to a finger.

For example, transmission measurement unit 50 may be clipped to fingertip 60 to measure transmission of SWIR radiation through finger tip 60.For example, the transmission measurement may be indicative of a medicalcondition, such as the concentration of a substance in blood that flowsthrough finger tip 60.

FIG. 2C schematically illustrates attachment of the measurement unit ofFIG. 2A to an ear.

For example, transmission measurement unit 50 may be clipped to outerear 62 to measure transmission of SWIR radiation through outer ear 62.For example, the transmission measurement may be indicative of a medicalcondition, such as the concentration of a substance in blood that flowsthrough outer ear 62.

In accordance with an embodiment of the present invention, a reflectionor transmission measurement may be utilized to characterize tissue in apatient.

A spectral reflectance measurement R(λ) may be expressed as

${R(\lambda)} = \frac{{I(\lambda)} - {B_{0}(\lambda)}}{{I_{0}(\lambda)} - {B_{0}(\lambda)}}$where I₀(λ) is a measured source intensity, I(λ) is a measured reflectedintensity, and B₀(λ) is a baseline measurement (e.g., measured wheninfrared radiation source 14 is turned off or when infrared detector 16is covered, e.g., by a shutter). Source intensity I₀(λ) may be monitoredcontinuously (e.g., by a dedicated detector), or may be measured in theabsence of tissue (e.g., a skin surface or body part) in the opticalpath from infrared radiation source 14 to infrared detector 16.

In some cases, baseline measurement B₀(λ) may be ignored when B₀(λ) ismuch smaller than I₀(λ) or I(λ).

The relative spectral absorbance A(λ), which may be used to characterizethe tissue, may be calculated by:

${A(\lambda)} = {{- {\log\mspace{11mu}\left\lbrack \frac{R(\lambda)}{\alpha_{R}} \right\rbrack}} \sim {- {\log\mspace{11mu}\left\lbrack \frac{I(\lambda)}{\alpha_{R}{I_{0}(\lambda)}} \right\rbrack}_{I,{I_{0}\operatorname{>>}B_{0}}}}}$where the dimensionless value A(λ)=α_(A)L is the relative spectralabsorbance, α_(A) is the absorption coefficient, L is the path-length ortissue penetration depth; and α_(R) is the reflection coefficient. Ingeneral, the relative absorbance A(λ) corresponds to spectralextinction, which results from both absorption and scattering.

Reflectance measurements in two or more spectral bands, Δλ_(i) may beperformed on a single region of skin or tissue to yield separatemeasured values of A(Δλ_(i)) or R(Δλi). For example, the spectral bandsmay include two or more of the wavelength ranges ˜1400 nm-1500 nm(strongly absorbed by water), ˜1000 nm-1350 nm (no strong absorption bywater), and ˜1500 nm-2100 nm (no strong absorption by water).

The differential absorption A_(Diff) may be calculated from measurementsin two wavelength bands, Δλ_(i) and Δλ_(j), where i≠j:

$A_{Diff} = {{{A\left( {\Delta\;\lambda_{i}} \right)} - {A_{ref}\left( {\Delta\;\lambda_{j}} \right)}} \sim {{\log\;\left\lbrack {R\left( {\Delta\lambda}_{i} \right)} \right\rbrack} - {\log\mspace{11mu}\left\lbrack {\Delta\;{R_{ref}\left( \lambda_{j} \right)}} \right\rbrack}} \sim {{\log\mspace{11mu}\left\lbrack \frac{R\left( {\Delta\;\lambda_{i}} \right)}{R_{ref}\left( {\Delta\;\lambda_{j}} \right)} \right\rbrack}.}}$

A_(ref) and R_(ref) refer the absorbance and reflectance in one of thespectral bands that serves as a reference band. For example, radiationin the reference band may be largely absorbed, scattered, or transmittedwhether or not a medical condition to be detected is present. Forexample, the wavelength range of ˜1400 nm-1500 nm (strong waterabsorption), a portion of this range, or another similarly unaffectedspectral range may be selected as the reference band.

Absorption, scattering, or transmission of radiation in one of the otherspectral bands, referred to as the operating band, may be detectablydependent on the presence of absence of the medical condition. Forexample, the operating band may include one or both of the spectralranges ˜1000 nm-1350 nm, ˜1550 nm-2100 nm, one or more portions of oneor both spectral ranges, or another suitable spectral range. Here, andthroughout the specification, the symbol ˜ indicates an approximation(e.g., ±10%).

The differential absorption may be related to the state of the tissue(e.g., presence, absence, degree, or other state of a medicalcondition). For example, a database of previous measurement results mayassociate a value of a differential absorption with a state of a medicalcondition such as inflammation (e.g., otitis media, or otherinflammation), tumor (e.g., in the colon, or elsewhere), or otherconditions. The differential absorption value may be used todifferentiate between conditions (e.g., inflammation and tumor, healthyand diseased tissue), detect or measure liquid within tissue, or otherconditions.

In some cases, reflection measurements may be made on a region of atissue surface when the underlying tissue is expected to be healthy(e.g., based on other medical indications), and another where presenceof unhealthy tissue is suspected.

The differential absorption A_(Diff) of two measurements with the samesetup and in the same wave-band Δλ_(i),i=1, 2, 3 yield two differentspectral absorbance values, A_(ref)(Δλ) and A_(SUS)(Δλ), whichcorrespond to healthy tissue (reference absorbance, A_(ref)) andsuspicious tissue A_(SUS), respectively:

$A_{Diff} = {{{A_{SUS}\left( {\Delta\;\lambda_{i}} \right)} - {A_{ref}\left( {\Delta\;\lambda_{i}} \right)}} \sim {{\log\mspace{11mu}\left\lbrack {R_{SUS}\left( {\Delta\;\lambda_{i}} \right)} \right\rbrack} - {\log\mspace{11mu}\left\lfloor {R_{ref}\left( {\Delta\;\lambda_{i}} \right)} \right\rfloor}} \sim {{\log\mspace{11mu}\left\lbrack \frac{R_{SUS}\left( {\Delta\;\lambda_{i}} \right)}{R_{ref}\left( {\Delta\;\lambda_{i}} \right)} \right\rbrack}.}}$

To improve detectability, all three spectral ranges Δλ_(i)i=1, 2, 3 canbe used simultaneously.

In some cases, chromophore content may be measured quantitatively. Insome cases, differentiation is limited to two states, e.g., healthy ordiseased (e.g., presence of pressure ulcer indicated by accumulation ofsubcutaneous liquid in the) tissue.

In some cases, a state of a medical condition (e.g., presence ofdiseased tissue) may be determined by calculating the tissue liquidindex (TLI), the sub-dermal fluid index (SDFI), or another quantity. Aparameter C, such as TLI, SDFI, or another parameter, can be defined asa normalized difference of the reflectance as measured at two differentwavelength bands Δλ_(i) and Δλ_(j), where i≠j:

$C = \frac{{R\left( {\Delta\;\lambda_{i}} \right)} - {R\left( {\Delta\;\lambda_{j}} \right)}}{{R\left( {\Delta\;\lambda_{i}} \right)} + {R\left( {\Delta\;\lambda_{j}} \right)}}$

In some cases, C may be approximated by

$C = {\frac{{R\left( {\Delta\;\lambda_{i}} \right)} - {R\left( {\Delta\;\lambda_{j}} \right)}}{R\left( {\Delta\;\lambda_{j}} \right)}\mspace{14mu}{or}}$$C = {\frac{R\left( {\Delta\;\lambda_{i}} \right)}{{R\left( {\Delta\;\lambda_{i}} \right)} + {R\left( {\Delta\;\lambda_{j}} \right)}}\mspace{14mu}{or}}$C = slope  [R(Δ λ)]

FIG. 3 shows an example of a graph of spectral reflectance.

Graph 70 shows measured reflectance in arbitrary units as a function ofwavelength. Normal tissue curve 72 may represent spectral reflectancefor normal, or healthy, tissue. Diseased tissue curve 74 may representspectral reflectance for diseased, or unhealthy, tissue. Water curve 76represents spectral transmittance for water (e.g., for a particularoptical path such as 1 mm; transmittance=1−absorbance) in arbitraryunits.

It may be noted that in the wavelength band of 1400 nm-1500 nm (lowwater reflectance due to strong absorption of radiation), there islittle difference between normal tissue curve 72 and diseased tissuecurve 74. However, in the adjacent bands (e.g., wavelength less thanabout 1350 nm), the difference is more pronounced.

Quantification of chromophores may enable estimation of changes inconcentration levels of substances or materials (e.g., drugs, or othersubstances) that may be administrated by injection, infusion, orotherwise.

The spectral transmittance of blood T_(B) may be expressed asT _(B)(λ)=I(λ)/I ₀(λ)=e ^(−(α) ^(B) ^((λ)+α(λ))·L)where α_(B)(λ) represents the absorption coefficient of blood and (e.g.,in units of cm⁻¹), respectively, at wavelength λ, α(λ) is the absorptioncoefficient of additional components of the tissue, and L is the lengthof the absorbing path (e.g., in cm). I(λ) is the detected intensity oftransmitted radiation, and I₀(λ) is the intensity of incident radiation.

Similarly, T_(% S), the spectral transmittance of a mixture of blood andan introduced substance may be expressed asT _(% S)(λ)=I(λ)/I ₀(λ)=e ^(−(α) ^(S) ^((λ)+α) ^(B) ^((λ)+α(λ))·L)where α_(S)(λ) represents the absorption coefficient of the introducedsubstance.

The absorption coefficients may relate to the concentrations of bloodC_(B) and of the introduced substance C_(S):α_(B)(λ)=ε_(B)(λ)·C _(B), andα_(S)(λ)=ε_(S)(λ)·C _(S).where ε_(B) and ε_(S) represent the absorptivity coefficients of bloodand of the introduced substance (e.g., in units of l·mol⁻¹·cm⁻¹ or1·g⁻¹·cm⁻¹; also referred to as the specific absorption coefficient ormass absorption coefficient), respectively.

The relative absorbance A_(S) (dimensionless) at wavelength λ may berelated to the concentration of introduced substance:

${A_{S}\left( {\lambda,C_{S}} \right)} = {{\log\mspace{11mu}\left( \frac{T_{\%\; S}}{T_{B}} \right)} = {\left( {{{ɛ_{S}(\lambda)} \cdot C_{S}} + {\alpha(\lambda)}} \right) \cdot {L.}}}$

The relative absorbance may be expressed as a linear equation:A _(S) =p ₁ ·C _(S) +p ₂with coefficient p₁ (e.g. in l·g⁻¹) and p₂ (dimensionless).

The normalized spectral transmittance S at a wavelength λ_(n) may becalculated from a measurement k as:

${S\left( {\lambda_{n},k} \right)} = \frac{{I_{meas}\left( {\lambda_{n},k} \right)} - {I_{dark}\left( \lambda_{n} \right)}}{{I_{ref}\left( {\lambda_{n},k_{0}} \right)} - {I_{dark}\left( \lambda_{n} \right)}}$

I_(meas)(λ_(n), k) is a measured radiation intensity at wavelength λ_(n)for measurement k, I_(meas)(λ_(n), k) being proportional to T_(% S).I_(ref)(λ_(n), k₀) is a reference signal for a measurement k₀ made priorto introduction of the substance into the blood, I_(ref)(λ_(n), k₀)being proportional to T_(B). I_(dark)(λ_(n)) represents a baselinemeasurement that is made in the absence of a radiation source, e.g.,when the radiation source is switched off.

The differential spectral absorbance A_(Diff) for measurement k at twowavelengths λ₁ and λ₂ may thus be calculated as

${A_{Diff}\left( {\lambda_{1},\lambda_{2}} \right)} = {{{A\left( \lambda_{1} \right)} - {A\left( \lambda_{2} \right)}} = {{{\log\mspace{11mu}\left\lbrack {S\left( {\lambda_{1},k} \right)} \right\rbrack} - {\log\left\lbrack {S\left( {\lambda_{2},k} \right)} \right\rbrack}} = {\log\mspace{11mu}\left\lbrack \frac{S\left( {\lambda_{1},k} \right)}{S\left( {\lambda_{2},k} \right)} \right\rbrack}}}$

For example, T_(B) and T_(% S) may represent relative spectraltransmittances of blood and of a mixture of blood and a introducedsubstance measured at two wavelengths λ₁ and λ₂:

${T_{B} = {\frac{T\left( \lambda_{1} \right)}{T\left( \lambda_{2} \right)} = e^{{- {({K_{B} + \alpha})}} \cdot L}}},{T_{\%\; S} = {\frac{T\left( \lambda_{1} \right)}{T\left( \lambda_{2} \right)} = {e^{{- {({K_{S} + K_{B} + \alpha})}} \cdot L}.}}}$

K_(B)=(α_(B)(λ₂)−α_(B)(λ₁)) and K_(S)=(α_(S)(λ₂)−α_(S)(λ₁)) representthe differential absorption coefficients of blood and of the introducedsubstance, respectively.

The relative differential absorbance A_(S) (dimensionless) at twowavelengths λ₁ and λ₂ is related to the concentration of introducedsubstance as:

${A_{S}\left( {\lambda_{1},\lambda_{2},C_{S}} \right)} = {{\log\mspace{11mu}\left( \frac{T_{\%\; S}}{T_{B}} \right)} = {\left( {{\left( {{ɛ_{S}\left( \lambda_{1} \right)} - {ɛ_{S}\left( \lambda_{2} \right)}} \right) \cdot C_{S}} + {\alpha(\lambda)}} \right) \cdot L}}$

The normalized spectral transmittance S at two wavelengths λ₁ and λ₂ maybe calculated from measurement k as:

${S\left( {\lambda_{1},\lambda_{2},k} \right)} = \frac{\left\lbrack {{I_{meas}\left( {\lambda_{1},k} \right)} - {I_{dark}\left( \lambda_{1} \right)}} \right\rbrack/\left\lbrack {{I_{meas}\left( {\lambda_{2},k} \right)} - {I_{dark}\left( \lambda_{2} \right)}} \right\rbrack}{\left\lbrack {{I_{ref}\left( {\lambda_{1},k_{0}} \right)} - {I_{dark}\left( \lambda_{1} \right)}} \right\rbrack/\left\lbrack {{I_{ref}\left( {\lambda_{2},k_{0}} \right)} - {I_{dark}\left( \lambda_{2} \right)}} \right\rbrack}$

The differential spectral absorbance A_(Diff) for measurement k at twowavelengths λ₁ and λ₂, then is:A _(Diff)(λ₁,λ₂)=log [S(λ₁,λ₂ ,k)]

The differential spectral absorbance measurement may eliminate theeffects of background materials. For example, if the absorption andscattering by the background materials (e.g., tissue components otherthan water, or a substance that is introduced into the blood) aresubstantially constant in both measured spectral bands, than thedifferential spectral absorbance may be indicative of the water contentof the tissue (e.g., as indicative of the presence or absence of amedical condition in which fluids accumulate in the tissue, orindicative of water content of blood).

A known relationship between the differential spectral absorbance and aconcentration of the substance in the blood may be applied to themeasured differential spectral absorbance to determine a concentrationof the substance in the blood. For example, the known relationship beapplied as a parameterized formula expressing the relationship (e.g., apolynomial or other formula), as a lookup table, or in another manner.

FIG. 4 shows a graph of an example of a relationship of absorbance toconcentration of a substance.

Line 82 of graph 80 shows a relationship between a relative absorbance(dimensionless) and the concentration of a substance (e.g., Propofol) inblood, as plotted on a logarithmic scale (e.g., in units of μg/ml). Therelationship may be derived from laboratory measurements 84, e.g., fromtransmission measurements on cuvettes containing various concentrationsof the substance in blood. A relationship may be derived by applicationof a fitting technique to fit line 82 to laboratory measurements 84.

FIG. 5 is a flowchart depicting a method for noninvasive analysis ofsubcutaneous liquids, in accordance with an embodiment of the presentinvention.

It should be understood with respect to any flowchart referenced hereinthat the division of the illustrated method into discrete operationsrepresented by blocks of the flowchart has been selected for convenienceand clarity only. Alternative division of the illustrated method intodiscrete operations is possible with equivalent results. Suchalternative division of the illustrated method into discrete operationsshould be understood as representing other embodiments of theillustrated method.

Similarly, it should be understood that, unless indicated otherwise, theillustrated order of execution of the operations represented by blocksof any flowchart referenced herein has been selected for convenience andclarity only. Operations of the illustrated method may be executed in analternative order, or concurrently, with equivalent results. Suchreordering of operations of the illustrated method should be understoodas representing other embodiments of the illustrated method.

Operations of subcutaneous liquid analysis method 100 may be executed bya processor of a controller of a device for subcutaneous liquidanalysis, or by a processor that is in communication with a controllerof a device for subcutaneous liquid analysis.

Execution of subcutaneous liquid analysis method 100 may be initiated bya user of a device for subcutaneous liquid analysis. For example, a usermay operate a control to initiate execution of subcutaneous liquidanalysis method 100. As another example, execution of subcutaneousliquid analysis method 100 may be initiated automatically when a devicefor subcutaneous liquid analysis is activated (e.g., turned on), andwhen it is detected (e.g., by an optical sensor or by a proximitysensor) that one or more apertures of the device are in contact with atissue surface.

The tissue may be irradiated with SWIR radiation in a spectral band thatis strongly absorbed by water (block 110). For example, a tissue surfacemay be irradiated with SWIR radiation in the wavelength range from about1400 nm to about 1500 nm. The radiation may originate from a widebandsource (e.g., an incandescent or other thermal source, or from afluorescent source), or from a narrowband source (e.g., laser diode orlight emitting diode). The irradiation may be filtered or otherwisemanipulated. For example, radiation that is emitted by a widebandradiation source may be filtered or otherwise manipulated to select onlythat radiation that is within the water-absorbed spectral band.

The tissue may be irradiated with SWIR radiation in a spectral band thatis adjacent to the water-absorbed spectral band (block 120). Forexample, a gap between the adjacent spectral band and the water-absorbedspectral band may be no more than 200 nm. In some cases, the gap may beno more than 100 nm. A single wideband source may produce both theradiation in the water-absorbed spectral band and in the adjacentspectral band. In some cases, the radiation in the adjacent spectralband may be isolated from radiation that is emitted by a wideband sourceprior to irradiation of the tissue.

Radiation that emerges from the tissue in each of the spectral bands maybe detected (block 130). The detector is configured to produce a signalthat is indicative of an intensity of the emerging radiation.

For example, one or more detectors may be configured to detect radiationthat emerges from the tissue surface that is irradiated. For example,optics of the radiation source and the radiation detector may be aimedat a single tissue surface. In this case, the detector is configured tomeasure backscattered or reflected radiation. As another example, thedetector may be configured to detect radiation that emerges from atissue surface on the opposite side of the tissue from the tissuesurface that is irradiated. In this case, the detector is configured tomeasure radiation that is transmitted by the tissue.

In some cases, different detectors may be configured to measure emergingradiation in each of the wavelength bands. For example, each detectormay be constructed of a material that produces an electric signal onlywhen irradiated with radiation in one of the spectral bands. As anotherexample, detector optics (e.g., including a filter or grating) mayrestrict radiation that is outside of that spectral band fromirradiating the detector. In some cases, the detector may be configuredto detect radiation in both spectral bands. In this case, separatemeasurement of the emerging radiation in the different spectral bandsmay be effected by separate (e.g., sequential or alternating)irradiation of the tissue with radiation in each of the spectral bands.In some embodiments, emerging radiation may be measured at differentdistances from a location of the irradiation. For example, emergingradiation may be measured concurrently by a plurality of detectors thatare arranged at different distances from a location on the tissuesurface that is irradiated. As another example, emerging radiation maybe measured sequentially in time at different distances by one or moredetectors whose distance from the location of irradiation may be changed(e.g., automatically or manually). In this case, a detector may beprovided with a sensor or mechanism (e.g., encoder or other sensor ormechanism) that is configured to measure a distance between a detectorand the radiation source. In some embodiments, signals received fromeach detector may correspond to the distance of the detector from thelight source. In some embodiments, the shape and/or intensity of asignal received by a detector may correspond to a medical condition inthe tissue, for example shape of a signal changed in measurements forhealthy tissue and for deep tissue injury, so that the shape of thesignal received for a healthy tissue changes when measuring an injuredtissue of the same subject (e.g., person). The shape of a signal maychange because of different types of chromophores and different types ofchemical functional groups on a chromophore. For example, a phenol ringon a chromophore will have different absorption graph shape incomparison to a CO chemical bond, CH chemical bond, or CN chemical bond.Absorption graph different shape means different location of theabsorption peak or peaks in different wavelengths and at different peakheights (amplitudes). In some embodiments, for a single detector theshape of a signal may refer to the intensity (or amplitude) ofabsorption lines as a function of the wavelength (e.g., at differentwavelengths). In some embodiments, for a plurality of detectors withdifferent distances from the radiation (or illumination) source, theshape of the signal may refer to a slope, such as the intensity (oramplitude) of absorption line at given wavelength for all detectors. Theprocessor may determine the change in shape of a signal by calculating(and/or testing) similarity of measured data sets with the predefineddata with known (or calibrated) spectral response (e.g., for healthytissue) and/or calculate a combined absorption graph (e.g., for aplurality of detectors). The similarity test may be performed by usingat least one of the following techniques: correlation coefficientestimation, minimum of signal difference at given wavelength orwaveband, t-test, Kruskal-Wallis test, Wilcoxon rank sum test,Kolmogorov-Smirnov test, etc. In some embodiments, a plurality ofdetectors may be used, each of the plurality of detectors may have adifferent distance from the radiation source. It should be appreciatedthat the signal received by each detector may have different amplitudes.According to some embodiments, the processor or controller may combinethe readings of the plurality of detectors and calculate the slope ofthe combined absorption graph (e.g., a graph that represents the resultof combining all detected amplitudes). A change in the state of thetissue may be determined, according to some embodiments, when a changein the slope of the combined absorption graph is detected (e.g., byprocessor 38 and/or controller 28 in FIG. 1).

Detection of the emerging radiation may be preceded by, followed by, ormay be concurrent with one or more calibration, baseline, or referencemeasurements. For example, a baseline or dark measurement may be madewhen the radiation source is not being operated. The baselinemeasurement may determine a signal that is produced by the detector(e.g., due to detector electronics or to stray radiation impinging onthe detector surface) when no radiation of interest is present. Acalibration measurement may be made when radiation that is emitted bythe source is directly (e.g., not via tissue) conveyed to the detector.Such a calibration measurement, when made concurrently with, orimmediately prior to or after, the measurement of emerging radiation mayenable compensation for drifting in source intensity or detectorsensibility. In some cases, a reference measurement may be made on theradiation that emerges from the tissue under known conditions (e.g., ona skin surface that is known to overlie healthy tissue, or prior tointroduction of a substance into the blood).

The measurements of emerging radiation may be used to calculate arelative absorption by the tissue (block 140).

For example, a relative reflectance may be calculated by calculating aratio of a measured intensity of reflected (e.g., due to backscattering)radiation in one of the spectral bands to the measured intensity ofreflected radiation in another spectral band. A relative absorption maybe inferred from the relative reflectance, e.g., on the assumption thata characteristic penetration depth of the radiation is the same in bothspectral bands. If the characteristic penetration depth of the radiationis known (e.g., from laboratory experiments), a differential absorbancemay be calculated.

A relative transmission may be calculated by calculating a ratio of ameasured intensity of transmitted radiation in one of the spectral bandsto the measured intensity of transmitted radiation in another spectralband. Since the path length through the tissue is the same for bothspectral bands, a relative absorption may be inferred from the relativetransmission. If the thickness of the tissue (L) is known (or may beestimated) and constant, a differential absorbance of the tissue may becalculated.

The relative differential absorbance A_(S) (dimensionless) at twowavelengths λ₁ and λ₂ is related to the concentration of introducedsubstance as:

${A_{S}\left( {\lambda_{1},\lambda_{2},C_{S}} \right)} = {{\log\mspace{11mu}\left( \frac{T_{\%\; S}}{T_{B}} \right)} = {\left( {{\left( {{ɛ_{S}\left( \lambda_{1} \right)} - {ɛ_{S}\left( \lambda_{2} \right)}} \right) \cdot C_{S}} + {\alpha(\lambda)}} \right) \cdot L}}$

According to some embodiments, Raman spectroscopy as described infurther detail below, may be employed to analyze the measurement data,and determine changes in concentration of any chemical compound insidethe tissue due to, for example, a deep tissue injury. The calculatedrelative absorption may be utilized to determine a state of the tissue(block 150). For example, a calculated differential absorbance, relativereflection, relative transmission, or other calculated value that isrelated to relative absorption may be compared to previously measuredvalues. The previously measured values may relate to a particular bodypart, suspected medical condition, introduced substance, or mayotherwise relate to a specific state that is being examined. Thecomparison may include substitution of the calculated value in afunctional relationship, may be used to retrieve an indication of thestate of the tissue from a lookup table, or may be otherwise utilized indetermining a state of the tissue.

It should be noted that deep tissue injuries may include presence ofliquids at depths larger than about 5 mm compared to a correspondingregion of a healthy tissue (e.g., of a healthy patient). Furthermore,deep tissue injuries may include increasing concentration (over time) ofsubstances that are products of ischemic processes (causing damage tothe tissue) such as free fatty acids and/or glycerol which are thebreakdown products of the fatty part of the tissue (triglyceride). Inthe blood stream (unlike other tissues) triglyceride may appear in theform of very low density lipoproteins (VLDL) while in other tissue thestructure of triglyceride is maintained. Accumulation of othersubstances (e.g., protease or myoglobin) may also indicate presence of adeep tissue injury. Therefore, in order to determine a state of deeptissue injury, calibration may be initially performed to identifysubstances in tissue indicating such an injury. Using the calculatedrelative absorption a state of deep tissue injury may be thereforedetermined, as described above.

According to some embodiments, a reflectance measurement may includedetecting reflected radiation at different lateral distances from aradiation source. In some embodiments, analysis of such reflectancemeasurements at different distances may indicate a depth within thetissue of a detected feature.

According to some embodiments, non-invasive measurement may be carriedout for determination of drug (e.g., intravenous delivered substancesuch as Propofol) or other substance concentration in the blood streamand/or in other subcutaneous tissue (e.g., of a mammal) using opticalsensors.

FIG. 6A schematically illustrates a system for measurement of reflectionat a distance from a radiation source, in accordance with an embodimentof the present invention.

According to some embodiments, reflection measurement system 200 mayinclude a source unit 202 and one or more detection units 204. Sourceunit 202 may include at least one infrared (IR) radiation source 14 andsource optics 18 a (e.g., lenses etc.) for directing a beam ofradiation, e.g., into a tissue surface 22. Each detector unit 204 mayinclude at least one IR detector 16 and detector optics 18 b (e.g.,lenses etc.) for directing radiation, for instance radiation emergingfrom tissue surface 22, toward infrared detector 16. Detector unit 204may be located at a measurement distance 206 from source unit 202. Forexample, measurement distance 206 may correspond to a distance between acenter of an aperture of source unit 202 to a center of detector unit204, and/or another measurement that characterizes a lateral distancebetween source unit 202 and detector unit 204.

In some embodiments, at least one of detector unit 204 and source unit202 (or assemblies that include a plurality of detector units 204 and/orsource units 202) may be moveable relative to one another so as tochange measurement distance 206. In this case, reflectance measurementsat different measurement distances 206 may be measured sequentially intime. The distance 206 between detector unit 204 and source unit 202 atthe time of a measurement may be determined with a dedicated mechanismand/or sensor. For example, detector unit 204 and source unit 202 may bemounted on a fixture that includes a mechanism for adjusting a distancetherebetween. The fixture may include a telescoping rod, a bendablejoint, or any other mechanism to adjust a distance between detector unit204 and source unit 202 in a controllable manner. The fixture mayinclude fixed stops at known distances between detector unit 204 andsource unit 202. Alternatively or in addition, a sensor may be providedto measure a distance between detector unit 204 and source unit 202. Forexample, a telescoping rod or bendable joint may be provided with anencoder to measure relative movement between detector unit 204 andsource unit 202. As another example, a rangefinder sensor may directlymeasure a distance between detector unit 204 and source unit 202.

In some embodiments, at least one source unit 202 and at least onedetector unit 204 may be combined in a single measurement unit toconcurrently measure radiation that emerges from tissue surface 22 atdifferent lateral distances from source unit 202.

FIG. 6B schematically illustrates an arrangement of a measurement headfor concurrent measurement of radiation that emerges from a surface atdifferent lateral distances from the radiation source, in accordancewith an embodiment of the present invention.

According to some embodiments, each measurement head 208 may include asingle source unit 202 surrounded by a plurality of detector units 204and separated by two different lateral distances form source unit 202.In the configuration shown in FIG. 6B, source unit 202 is surrounded byan arrangement of inner detector units 204 a, each laterally separatedfrom source unit 202 by a distance that is substantially equal to firstdistance 206 a. Inner detector units 204 a are surrounded by anarrangement of outer detector units 204 b, each separated from sourceunit 202 by a lateral distance that is substantially equal to seconddistance 206 b. In some embodiments, second distance 206 b may be largerthan first distance 206 a.

It should be noted that the arrangement shown in FIG. 6B has beenselected for illustrative purposes only. An actual arrangement maydiffer from the arrangement shown in FIG. 6B. For example, anarrangement may include detector units 204 at more than two distancesfrom a source unit 202. An arrangement may include a different patternof detector units and/or of source units. An arrangement may includemore than one source unit 202. For example, different source units 202may produce radiation with different wavelengths. A center unit mayinclude a detector unit 204 (e.g., surrounded by sources 202).

In some embodiments, measurement of a distance to a detected feature maybe advantageous. For example, measurement of a distance may enabledifferentiation between a superficial pressure ulcer and a deep ulcer.In some embodiments, such measurement of a distance may enabledifferentiation between a deep pressure injuries and superficialpressure ulcers. In some embodiments, a distance between the lightsource and the light sensor may be predetermined. In some embodiments,determination of such distance may allow determination of a medicalcondition in the tissue (e.g., deep tissue injury) due to changes insignal from a detector having a determined distance to the light source.

Pressure ulcers are areas of soft tissue breakdown that result fromsustained mechanical loading of skin and underlying tissues. They caninterfere with quality of life, activities of daily living, andrehabilitation and, in some cases, may be life threatening. Pressureulcers can develop either superficially or deep within the tissues,depending on the nature of the surface loading and the tissue integrity.The superficial pressure ulcer type forms within the skin, withmaceration and detachment of superficial skin layers. When allowed toprogress, the damage may result in an easily detectable superficialulcer.

In contrast, deep tissue ulcers arise in muscle layers covering bonyprominences and are mainly caused by sustained compression of tissue.Deep tissue ulcers may develop at a faster rate than superficial ulcers,and result in more extensive ulceration with an uncertain prognosis.

In addition to absorption of radiation that traverses tissue, NIR andSWIR radiation may be strongly scattered by such tissue. The freescattering length may be in the range of about 0.3 mm to about 1 mm. Insome embodiments, the scattering may be strongly forward peaked. Beyonda free transport scattering length (e.g., about 1 mm), directionalcorrelation with the direction of the incident irradiation (thecorrelation between the actual direction and the direction of incidence)is lost such that radiation transport may be modeled as photondiffusion. In a photon diffusion model, scattering may be isotropic atlocations that are more distant from radiation sources and boundariesthan several times the free scattering length. Photons may followcomplex trajectories that are considerably longer than the geometricaldistance between the radiation source and the radiation detector.

FIG. 7 schematically illustrates paths of incident radiation todifferent detector locations, in accordance with an embodiment of thepresent invention.

According to some embodiments, a deep lesion 210 (or other deep tissueinjury) may be distant from tissue surface 22. Incident radiation 214may enter tissue surface 22 (e.g., from a source unit 202 as shown inFIG. 6A). Emerging radiation 216 a, 216 b, and 216 c may emerge fromtissue surface 22 at different distances from incident radiation 214,having traversed radiation paths 218 a, 218 b, and 218 c respectivelywithin the tissue. It should be noted that as shown in FIG. 7, onlyradiation path 218 c passes through deep lesion 210. Thus, only emergingradiation 216 c may correspond to and be attenuated by water absorptionin deep lesion 210.

According to some embodiments, a connection between measured absorptionand differences in concentration of subcutaneous liquids may bedescribed with reference to a modified Beer-Lambert law:

${A(\lambda)} = {{- {\log\mspace{11mu}\left\lbrack {{I(\lambda)}/{I_{0}(\lambda)}} \right\rbrack}} = {{\left( {{ɛ_{water}C_{water}} + {\sum\limits_{i}{ɛ_{i} \cdot C_{i}}} + \mu_{S}} \right) \cdot} < L >}}$where I₀(λ) is a measured source intensity, I(λ) is a measured reflectedintensity, A(λ) is the measured absorption (attenuation), ε_(water) isthe absorptivity coefficient of water, C_(water) is the concentration ofwater, and ε_(i) and C_(i) are the absorptivity coefficients andconcentrations of different absorbing compounds. The path length<L>˜(F·d) represents the total mean optical path in the tissue (e.g., inunits of centimeters), where d is the distance between the point ofincident radiation 214 and one of emerging radiation 216 a, 216 b, or216 c, and F is a scaling factor (related to the optical path length).The scattering coefficient may be expressed as μ_(s)=μ_(s0)(1−g), whereg is the scattering anisotropy.

For example, it may be assumed that the ratio for a penetration depthbelow tissue surface 22 may be twice the lateral distance d between thepoints of incident radiation 214 and the emerging radiation 216 a, 216b, or 216 c.

Differences in concentration of subcutaneous liquids may be estimatedfrom the slope (ΔA/Δd) of the attenuation with respect to distance d,where A₁−A₂≡ΔA=ε·(ΔC·<L>), with A₁ and A₂ representing differentialabsorptions A_(Diff) as described above that are measured with twodifferent lateral distances d between incident radiation 214 andemerging radiation 216 a, 216 b, or 216 c.

In some embodiments, the change in differential measurements may beanalyzed to obtain ΔA/ε=ΔC<L>. When the relationship between path length<L> and lateral distance d is known, the measurements may be analyzed toyield a change in concentration of water.

According to some embodiments, Raman spectroscopy may be employed toanalyze the measurement data. In Raman spectroscopy a complementaryscattering mechanism to excite the molecules into the vibrational statesmay be achieved via the visible excitation wavelengths. Raman scatteringmay be an inelastic scattering which is usually generated by intensivemonochromatic light (e.g., laser) in the visible, near infrared, or nearultraviolet (UV) region. The energy of laser photons may be changedafter the excitation laser interacts with the vibrating molecules or theexcited electrons in the sample. As a spontaneous effect, photons maytransfer the excitation energy to change the molecule from the groundstate to a virtual state. The excited molecule may then return to adifferent rotational or vibrational state after emitting a photon.

As may be apparent to one of ordinary skill in the art, the differencebetween wavelengths of photons in the incident wavelength λ₀ (excitationwavelength) and the scattered light is known as a Raman shift. It isrelated to characteristic oscillation frequencies of the molecule, andmay correspond to the oscillations of a single molecular bond or thelarger fragment of a molecular network. For λ₀ far from the moleculeabsorption band, intensity of the Raman signal may be inverselyproportional to λ₀ ⁴ so application of a VIS or UV laser as theexcitation source may be more effective than an IR one if the intensityof Raman scattering was considered. However, practical efficiency ofRaman scattering versus excitation wavelength may also depend ondimensions of the investigated structures.

Moreover, fluorescence induced by the laser beam maybe also taken intoaccount. Fluorescence is the strongest for the excitation wavelength λ₀range extending from 270 to 700 nm but its influence can be differentfor various materials. It is particularly strong for organic materials,so the excitation range in VIS and near UV is not appropriate for theirsampling.

In some embodiments, application of NIR lasers (e.g., in the range of785-1064 nm) may be effective with selection of appropriate detectortypes (e.g., InGaAs, MCT, etc.) that can ensure high efficiency of themeasurement system in a wide Raman range of 800 cm⁻¹ to 4000 cm⁻¹. Ramanrange of systems using such detectors may begin at about 800 cm⁻¹ forexcitation wavelength equal to 830 nm.

In some embodiments, a measurement system (such as reflectionmeasurement system 200 shown in FIG. 6A) to employ Raman spectroscopymay include at least one light source (e.g., such as source unit 202shown in FIG. 6A). The source unit may include a diode laser (e.g., ˜100mW), light emitting diodes (LEDs) and/or a combination thereof. In someembodiments, Raman measurement system may include at least one lightsensor (e.g., such as detection unit 204 shown in FIG. 6A). The lightsensor may include a thermoelectric cooled charge coupled detector (CCD)and/or a spectrograph. In some embodiments, the Raman measurement systemmay include optical elements (e.g., such as optics 18 a, 18 b shown inFIG. 6A) with at least one of beam expanding/focusing lenses, laser-linefilter, dichroic mirrors, holographic rejection (notch) filters, low-pasfilter, and fibers. In some embodiments, at least two elements of theRaman measurement unit may be embedded in a plastic polymer casingwithin a wrist band which positions the sensing unit firmly above awrist blood vessel. The unit may be wirelessly connected to an externalprocessor such as external device 30 shown in FIG. 1A (e.g., viaBluetooth protocol). In some embodiments, in order to reduce theinfluence of background fluorescence signal, the 830 nm excitationwavelength may be used. According to some embodiments, Raman measurementsystem may indicate a change in concentration of a chemical compoundwithin the tissue, for example due to deep tissue injury aftercalibration with healthy tissue is carried out.

According to some embodiments, a Raman measurement system may include atleast one processor (such as controller 28 shown in FIG. 1A) and/orcommunicate with at least one processor (such as external processingdevice 30 shown in FIG. 1A) so as to allow analysis of the measured dataaccording to Raman spectroscopy. In some embodiments, such analysis mayinclude measurements of the distance between the light source and thelight sensor. In some embodiments, such analysis may allow determinationof liquid accumulation and/or determination of concentration of chemicalcompounds within the tissue (e.g., myoglobin, triglycerides, proteins,etc) and thereby determine deep tissue injuries if a change in theconcentration corresponds to deep tissue injuries. In some embodiments,such analysis may allow determination of at least one substance secretedas a result of a deep tissue injury.

In some embodiments, the changes in the spectra (e.g., change inintensity of absorption spectra over time) of blood with Propofolmixture may overlap with the most prominent lines of the Propofolsolution, for instance at spectral regions: 875 cm⁻¹-1050 cm⁻¹, 1250cm⁻¹-1260 cm⁻¹, and 1450 cm⁻¹.

The Raman intensity may be 10⁻⁶ to 10⁻⁹ times less than that of Rayleighscattering. Therefore, well-controlled high-power light sources (e.g.,˜100 mW) and sufficient accumulation time (e.g., tens of a second) maybe required in order to produce a sufficient number of Raman-scatteringphotons. In the IR spectroscopy, abundance of water in most biologicalenvironments, a very strong IR absorption by water may interrupt theemitted photons of the target. In contrast, a weak Raman scattering bywater may have detection of bio-molecular signals in water-abundanceenvironments, such as body fluids, cells and/or other tissues.

According to some embodiments, a controlled cyclic change in externalconditions applied on a region of the skin may also allow determinationof deep tissue injuries. In some embodiments, applying pressure (e.g.,measuring with a pressure sensor) in varying magnitude and/or applyingheat (e.g., measuring with a temperature sensor) in varying magnitudemay cause different absorption and/or scattering of radiation in tissueswith deep tissue injuries (compared to absorption and/or scattering inhealthy tissue). For example, pressure may be applied in a periodical(e.g., sinusoidal) regime to determine presence of a deep tissue injury.

In some embodiments, an at least partially transparent (to visibleand/or IR radiation) biodegradable element, for instance an elastomer orother soft plastic, may be placed upon the at least one radiationdetector as a cover so as to allow protection of sensors (e.g., fromgels applied on the skin). In some embodiments, such biodegradableelement may be transparent at least 90%.

According to some embodiments, specific regions of a measured MIR may becompared to VIS-NIR-SWIR spectrum for non-invasive monitoring ofsubstance concentration (e.g., Propofol, etc.) in tissue (e.g., inblood). In some embodiments, substances that exhibit uniqueVIS-NIR-SWIR-MIR signatures during measurements may be monitored. Insome embodiments, the spectral signatures may be used as input formultivariate classification in order to automatically quantify and/oridentify the response. The multivariate classification methods mayinclude at least one of partial-least square (PLS), principal componentregression (PCR), linear discriminant analysis (LDA), k-nearestneighbors (kNN), naive bayesian classifier (NBC), support vector machine(SVM), artificial neural networks (ANN), etc. Spectral attenuation(e.g., in the VIS-NIR-SWIR range) in tissue may occur due to absorptionfrom chromophores (e.g., of fixed or variable concentration) and/or dueto scattering from the tissue. In some embodiments, absorption andscattering properties of the tissue may be characterized by absorption(μa) and scattering (μs) coefficients as: μa˜εC and μs=μs0(1−g), where‘ε’ is the absorptivity, ‘C’ is the concentration of absorbingcompounds, and ‘g’ is the scattering anisotropy. The spectralattenuation (e.g., due to absorption) may be represented as:A(λ)=−log [I(λ)/I ₀(λ)]=(Σε·C+μ _(s))·<L>where ‘I(λ)’ is the detected intensity of transmitted and/or scatteredradiation, I₀(λ) is the intensity of incident radiation, <L>˜(F·d) isthe total mean optical path in the tissue (in centimeters), ‘d’ is thedistance between the light source and the detector, and ‘F’ is thescaling factor as a function of (μs, μa, g). For example, absorptionand/or scattering for soft tissues (e.g., for skin) in the range of800-1300 nm may be μa˜0.1-2 cm⁻¹ and μs˜1-25 cm⁻¹.

According to some embodiments, some substances (e.g., Propofol) may haveunique effect on the absorption properties of the blood, such that thesesubstances may be monitored within the blood stream in particular. Insome embodiments, the spectral transmittance of blood ‘T_(B)’ may beexpressed as:T _(B)(λ)=I(λ)/I ₀(λ)=e ^(−(α) ^(B) ^((λ)+α(λ))·L)where α_(B)(λ) is the absorption coefficient of blood (e.g., in units ofcm⁻¹) at wavelength λ, α(λ) is the absorption coefficient of othercomponents of the tissue, and ‘L’ is the length of the absorbing path(e.g., in centimeters). ‘I(λ)’ is the detected intensity of transmittedradiation, and ‘I₀(λ)’ is the intensity of incident radiation.

In some embodiments, the spectral transmittance of a mixture of bloodand an introduced substance (e.g., Propofol) ‘T_(% S)’ may be expressedas:T _(% S)(λ)=I(λ)/I ₀(λ)=e ^(−(α) ^(S) ^((λ)+α) ^(B) ^((λ)+α(λ))·L)where α_(S)(λ) is the absorption coefficient of the introducedsubstance.

In some embodiments, the absorption coefficients may relate to theconcentrations of blood ‘C_(B)’ and the introduced substance‘C_(S)’:α_(B)(λ)=ε_(B)(λ)·C_(B), and α_(S)(λ)=ε_(S)(λ)·C_(S). where‘ε_(B)’ and ‘ε_(S)’ represent the absorptivity coefficients of blood andof the introduced substance (e.g., in units of liter·mol⁻¹·cm⁻¹ orliter·g⁻¹·cm⁻¹, also referred to as the specific absorption coefficientor mass absorption coefficient), respectively.

In some embodiments, the relative absorbance ‘A_(S)’ at wavelength ‘λ’may be related to the concentration of introduced substance as a linearequation:

${A_{S}\left( {\lambda,C_{S}} \right)} = {{{- \log}\mspace{11mu}\left( \frac{T_{\%\; S}}{T_{B}} \right)} = {{{- \left( {{{ɛ_{S}(\lambda)} \cdot C_{S}} + {\alpha(\lambda)}} \right)} \cdot L} = {{p_{1} \cdot C_{S}} + {p_{2}.}}}}$

In some embodiments, the normalized spectral transmittance ‘S’ at awavelength ‘λ_(n)’ may be calculated from a measurement ‘k’ as:

${S\left( {\lambda_{n},k} \right)} = \frac{{I_{meas}\left( {\lambda_{n},k} \right)} - {I_{dark}\left( \lambda_{n} \right)}}{{I_{ref}\left( {\lambda_{n},k_{0}} \right)} - {I_{dark}\left( \lambda_{n} \right)}}$where I_(meas)(λ_(n), k) is a measured radiation intensity at wavelengthλ_(n) for measurement ‘k’, I_(meas)(λ_(n), k) being proportional to‘T_(% S)’ as described above. I_(ref)(λ_(n), k₀) is a reference signalfor a measurement ‘k₀’ made prior to introduction of the substance intothe blood, I_(ref)(λ_(n), k₀) being proportional to ‘T_(B)’ as describedabove. I_(dark)(λ_(n)) represents a baseline measurement that may bemade in the absence of a radiation source (e.g., when the radiationsource is switched off).

In some embodiment, the change concentration (e.g., of Propofol) due totransmission and/or reflection may be estimated from the differences inattenuation between two blood states:

${\Delta\;{A(t)}} = {{{A_{B - P}(t)} - {A_{B}\left( t_{0} \right)}} = {{\log\left( \frac{I_{B}}{I_{B - P}} \right)} = {< L > {{{\cdot ɛ_{P} \cdot \Delta}\; C_{P}} + G}}}}$where A_(B)(t0) is the spectral attenuation without the substance (e.g.,Propofol), A_(B-P)(t) is the spectral attenuation with blood-substancemixture, <L> is the mean path-length, ‘ε_(P)’ is the absorptivity of thesubstance (e.g., Propofol), ΔC_(P) is the concentration difference forthe substance (e.g., Propofol), and G is a constant dependent on atleast one of μs, μa, g, and measurement geometry. In some embodiment,the differences in attenuation between two blood-substance states may beestimated from the slope (ΔA/Δt) of the attenuation with respect to time‘t’, where:A ₁ −A ₂ ≡ΔA=ε·(ΔC·<L>),where ‘A₁’ and ‘A₂’ represent absorptions that are measured at twodifferent time units with a given lateral distance between incidentradiation and emerging radiation.

According to some embodiments, some measurements may be carried out withdetection of transmission radiation, for instance radiation passingthrough the ear (e.g., using the transmission measurement unit 50 asshown in FIGS. 2A-2C). In some embodiments, a transmission measurementunit may include at least one of a light source (e.g., in VIS-NIR-SWIRrange), optical elements (e.g., collimating lenses, filters, focusinglenses), a detector (e.g., for the VIS-NIR-SWIR range), spectrometer, amotion sensor (e.g., gyro, accelerometer, etc.), and an attachablesegment (e.g., a clip). In some embodiments, the attachable segment maybe configured to attach at least one light source and corresponding atleast one sensor to be aligned accurately against each other from bothsides of ear cartilage.

In some embodiments, the attachable segment (e.g., ear clip) may includeadhereable tips configured to allow stable positioning on the earcartilage. In some embodiments, at least one of the light source andcorresponding sensor may include a (thin) plastic polymer shaped in anergonomic half disc shape, so as to allow easy positioning of the clipinside the round curvature of the ear cartilage border.

In some embodiments, the at least one sensor may be battery operatedand/or with a wireless connectivity protocol (e.g., Bluetoothconnectivity). The ear clip may contain the sensing unit on one arm andthe light source unit on the other arm. The ear clip may include anadjustment knob to regulate pressure on ear cartilage avoiding overpressure which reduce blood flow in the ear cartilage capillaries. Insome embodiments, the transmission measurement unit may include a motionsensor with a corresponding algorithm configured to adjust (and orcompensate) to sudden movements during measurements. For example, acompensating mechanism may stop the measurements during movement of thesubject and/or calculate and/or interpolate missing readings for themeasurements.

According to some embodiments, some measurements may be carried out withdetection of reflected radiation, for instance measuring backscatteredradiation. In some embodiments, a reflectance measurement unit mayinclude at least one of a light source (e.g., in VIS-NIR-SWIR range),optical elements (e.g., collimating lenses, filters, focusing lenses), adetector (e.g., for the VIS-NIR-SWIR range), spectrometer, one or moremotion sensors (e.g., gyro, accelerometer, etc.), and an attachablesegment (e.g., guide wire attachable on a limb of the subject). In someembodiments, the attachable segment may be configured to be attached ona limb with at least one light source and corresponding at least onesensor to be aligned in proximity to topical blood vessels (e.g.,carotid arteries, jugular veins, grate saphenous veins, cephalic vein,arcuate arteries, etc.). In some embodiments, the reflectancemeasurement unit may include a motion sensor with a correspondingalgorithm configured to adjust (and or compensate) to sudden movementsduring measurements. It should be noted that patients administered withPropofol are known to move during anesthesia due to short duty cycles ofPropofol, and sudden (e.g., mechanical) movements during measurementsmay alter the optical absorption and/or reflection signal. In order tomake sure that signal change is received from mechanical movements(e.g., and not from a heart attack) a movement sensor may be attached tothe limbs or head so as to detect and compensate sudden movements duringmeasurements. For example, a compensating mechanism may stop themeasurements during movement of the subject and/or calculate and/orinterpolate missing readings for the measurements.

FIG. 8 is a block diagram showing elements of a measurement unit, inaccordance with an embodiment of the present invention. A measurementunit 300 (e.g., optical transmission and/or reflectance unit) may beused to measure signals of the body in order to determine concentrationof predetermined substances (e.g., Propofol). The measurement unit 300may include a central controller or processor 301 (e.g., such ascontroller 28 shown in FIG. 1A), at least one light source 302, and atleast one light sensor 303. In some embodiments, measurement unit 300may further include at least one motion sensor 304 and/or an attachablesegment 305 (e.g., a clip) configured to be attach to a portion of thebody of the patient.

In some embodiments, at least one light source 302 may be coupled to atleast one optical element 306 (e.g., collimating lenses, filters,focusing lenses), and at least one light sensor may be coupled to aspectrometer 307. Processor 301 may communicate (e.g., receive and/orsend signals) with coupled elements (such as the light source and/or thelight sensor) and analyze the received measurement data. Processor 301may communicate (e.g., receive and/or send signals) with an externaldevice using a communication module 308 (e.g., via Bluetooth).

According to some embodiments, measurements may be carried out withattenuated total reflection (ATR) spectroscopy using optical elementsand/or sensors operated in the ATR regime in the range of 4000 cm⁻¹ to400 cm⁻¹ (or 2.5 um to 25 um). In some embodiments, analysis of suchmeasured data may be carried out with evanescent wave Fourier transforminfrared (EW-FTIR) spectroscopy and/or FTIR-ATR spectroscopy.

As may be appreciated by someone with ordinary skill in the art, in theMIR range some fundamental molecular vibrations may occur as well asmany of the first overtones and combinations thereof. The spectral bandsin the MIR range tend to be sharp and may have high absorption. Sincethe bands are sharp, most small molecules may have distinctive spectral“fingerprints” that can be readily identified in mixtures (e.g., amixture of Propofol and blood). Moreover, since individual peaks canoften be associated with individual functional groups, it may bepossible to detect changes in the spectrum of individual objects duringthe monitoring due to the corresponding specific reaction.

Fourier transform infrared (FTIR) spectroscopy is based on theinteraction between the radiation and the sample (e.g., Propofol), whichabsorbs the IR wavelengths causing transitions between vibrationalenergetic levels, and thus vibrational modes of different chemical bondsand/or molecules may be detected.

According to some embodiments, the FTIR-ATR spectroscopy may utilize thetotal internal reflection phenomenon, occurring when a beam of radiationenters from a denser medium with a higher refractive index, n₂, into aless-dense medium with a lower refractive index, n₁. In FTIR-ATRspectroscopy a crystal with a high refractive index and IR transmittingproperties may be used as internal reflection element (or an ATRcrystal). The ATR element 309 may be placed in contact with the sample(e.g., liquids or a moist epithelial tissue).

In some embodiments, the beam of radiation propagating in ATR mayundergo total internal reflection at the interface of ATR-sample. Totalinternal reflection of the light at the interface between the two mediaof different refractive index (crystal-tissue) may therefore create an“evanescent wave” that penetrates into the medium of lower refractiveindex (or tissue). The intensity of evanescent waves may decayexponentially with distance from the interface at which they are formed.Such distance may be for example in the 1-25 um range.

In some embodiments, the evanescent wave may be attenuated in regions ofthe spectrum where the sample absorbs energy, and the attenuated energymay be passed back to the optical element. The radiation may then exitthe optical element and impinge on a detector through optical waveguideand/or fiber. The detector may record the attenuated radiation, whichmay be transformed to generate a spectrum (e.g., an absorption spectra).

The depth of penetration ‘dp’ into the sample of the evanescent wave maybe defined as the distance from the ATR-sample boundary where theintensity of the evanescent wave decays to about 1/e (or 37% of itsoriginal value), and may be represented as:dp=(n _(ATR) ² sin² θ−n _(S) ²)^(−1/2) /k,k=2π/λwhere ‘λ’ is the wavelength of the radiation, ‘θ’ is the angle ofincidence of the wave front (or light beam), and ‘n_(ATR)’ and ‘n_(S)’are the refractive indices of ATR element and sample respectively.

The sample under test may be placed in tight contact with the ATRelement along the IR radiation pathway, between the source and thedetector side. When the ATR element is in contact with the sample, theevanescent wave may be either partially or totally absorbed at specificabsorption lines as determined by the biochemical composition of thesample. The total transmission through the ATR element and the samplemay decrease at the absorption lines that correspond to molecular bondsin particular classes of bio-molecules. In some embodiments, a coresilver halide fiber may be used as the ATR element, since thepolycrystalline silver halide (e.g., AgClxBr1-x) fibers are useful forapplications in the mid-IR. These fibers may have a wide transparencyrange (˜2-20 um wavelength), they are non-toxic, flexible and may beinsoluble in water.

According to some embodiments, FTIR-ATR unit may include a centralcontroller or processor (e.g., such as processor 301 shown in FIG. 8),at least one IR light source (e.g., such as light source 302 shown inFIG. 8), for instance a broadband IR source for emitting an IR beam intothe ATR element 309. In some embodiments, the FTIR-ATR unit may includeat least one light sensor (e.g., such as light sensor 303 shown in FIG.8), for instance a beam delivery and collection optics (e.g., a guidewire or fiber).

In some embodiments, the FTIR-ATR unit may include ATR element 309 atthe tip of a guide wire (e.g., embedded in a clip arm, such asattachable segment 305 shown in FIG. 8) thereby positioning the ATRelement 309 in an intimate fixed contact with a moist epithelial tissue,for instance of the inner lower or upper lip (where there is no stratumcorneum). Such a clip may have for example a curved arced shape with theATR element 309 embedded on the clip arm in such a way that the curvepositions the ATR probe on the inner lower or upper lip. In someembodiments, the FTIR-ATR unit may include an FTIR spectrometer (e.g.,such as spectrometer 307 shown in FIG. 8) and/or IR sensors forsimultaneously measuring absorbance of specific regions of the IRspectrum.

The ATR tip may have different forms: for example loop, flat form,lens-like form, hexagon, triangle, etc. The ends of ATR element may beconnected to the IR source and detecting system by using the waveguidefor the FTIR-ATR device implementation. In some embodiments, the ATRelement may be configured to allow multiple internal reflections (e.g.,3-15 internal reflections) against the measurement surface prior tomeasurement by the IR sensors.

According to some embodiments, an ATR element may be placed withinrunning urine in a urine collecting catheter or in the urine collectingbag in order to preform measurements of the urine. In some embodiments,the ATR element frontal surface may be dipped in the urine stream whilethe rest of the ATR element may be embedded in the plastic polymercatheter tube or bag.

According to some embodiments, in order to receive the benefit from thedata of concentration of a particular substance (e.g., Propofol) in theblood stream there may be a need to combine the substance (e.g.,Propofol) readings with other parameters of the patient, for instanceutilizing an algorithm which combines a set of parameters. According tosome embodiments, in order to quantify concentration of anesthetic drugs(e.g., Propofol, etc.) and/or identify and/or classify deep tissueinjury (DTI), the algorithm may use the multivariate classificationmethods, for instance including at least one of partial-least square(PLS), principal component regression (PCR), linear discriminantanalysis (LDA), k-nearest neighbors (kNN), naive bayesian classifier(NBC), support vector machine (SVM), artificial neural networks (ANN),etc. In some embodiments, such a process may include training (orcalibration) and validation steps. The Propofol concentration (e.g., ing/mL, mol/mL, etc.) may be considered as the dependent variables (‘Y’),and the other variables (e.g., data matrices A, B, C, D, E) may be theindependent variables (‘X’). Data matrices A, B, C, D, and E may referto the matrices of measured values: such as the spectral dataset withRaman data (matrix A), FTIR-ATR data (matrix B), reflectance mode data(matrix C), transmittance mode data (matrix D) and deterministic and/orvital signs parameters (matrix E). The multivariate classification(e.g., with multiple regression) may allow finding a solution that bestpredicts the ‘Y’ variable as a linear (or non-linear) function of the‘X’ variables. For example, the general equation for the multipleregression may be for example:

$Y = {{b_{0} + {b_{1}x_{1}} + {\ldots\mspace{14mu} b_{k}x_{k}} + f} = {{b_{0} + {\sum\limits_{i = 1}^{k}{b_{i}x_{i}}} + f} = {b_{0} + f + {BX}}}}$where ‘Y’ is the response (e.g., Propofol concentration), x_(k) are thepredictors (A, B, C, D, and E), bk are the regression coefficient to bedetermined, b₀ is the offset and a constant factor, and ‘f’ is theresidual. If ‘X’ and ‘Y’ are mean-centered, then b₀=0. This equation mayalso be written in matrix form: Y=Xb+f.

The parameter ‘b’ may be estimated for example by a least squares (LS)fit minimizing the sum of squared residuals, where multiple linearregression (MLR) may be used for estimating the regression vector ‘b’.The solution for regression coefficient for the LS may be for example:b=(X^(T)X)⁻¹X^(T)Y, where ‘T’ refers to the transpose of the matrix. Insome embodiments, after training and/or validation the regressioncoefficients bk may be determined and/or stored. In some embodiments,the processor may use the coefficients bk during the real-timequantification of changes in concentration of anesthetic drugs in bloodduring the anesthesia.

Deterministic parameters may include the patient's age, gender, weight,bio mass index (BMI), background diseases, and other changing parametersof vital signs such as temperature, breathing rate, blood pressure,PO₂-pulse oximetry, EEG, bi-spectral index (BIS), signal sensors andpatient movements (e.g., measured with a gyro) to create a minimalanesthetic concentration (MAC) model.

The recombined set of parameters may continuously or iterativelydetermine (e.g., in a closed loop controlled process of continuousmeasurements) the minimal dose of substance (e.g., Propofol) forinjection to achieve the desired anesthetic effect. It should be notedthat the combination of the standard vital signs and other parameterswith substance (e.g., Propofol) concentration data in real time and thealgorithm which controls the syringe pump may provide optimalmeasurements. The movement sensors (e.g., gyro and/or accelerometers)may be combined in a wrist band, a leg band, or a temporal band (alongthe temporal bone), and wirelessly communicate with the main CPU (e.g.,such as such as processor 301 shown in FIG. 8 or external device 30shown in FIG. 1A), for instance via Bluetooth protocol.

According to some embodiments, a measurement system may include ameasurement unit (e.g., as shown in FIG. 8) such as a transmission unit,a reflectance unit, FTIR_ATR unit, Raman unit, and urine collectionunit. The measurement unit may also receive parameters of the subjectbody (e.g., vital signs) measured with dedicated sensors. Themeasurement unit may include at least one optical sensor unitspositioned at least on one wrist and/or on the mouth lip and/or on theouter ear and/or on the leg and/or in a urine collection catheter orbag. Each sensor may be operated simultaneously and/or simultaneouslycollect data from different sensors. The collected data may betransmitted to a main CPU (e.g., such as processor 301 shown in FIG. 8or external device 30 shown in FIG. 1A) which may process the datatogether with data collected from other vital sign sensors and otherpreprogrammed data to control continuous injection of the substance(e.g., Propofol) to the patient.

In some embodiments, the sensors which are located on the wrist band(e.g., via a sticker) may have a transparent casing polymer to allowmeasuring blood vessel on the wrist therethrough. The sensing unit mayinclude at least one light source and at least one light sensor (e.g.,positioned 2-3 mm next to each other) and positioned perpendicular to awrist blood vessel. In some embodiments, the light source may detect theposition of the blood vessel (using strongest absorption measurementanalysis), for instance using at least one of visible and NIR light.

In some embodiments, the at least one sensor may be mounted on atransparent plastic polymer in a rotatable dial with an open slit of 4-6mm wide along its diameter axis allowing a good view of the wrist bloodvein from a top view and allowing positioning by rotation of the dialwith sensors and light sources in such a way that the light sources andsensors may be aligned above a wrist blood vessel. In some embodiments,the sensors may have an external ring that is adhered to the skin aroundthe blood vessel. In some embodiments, the measurement unit is batteryoperated and has a wireless communication module.

It should be noted that analysis (e.g., with a processor such asprocessor 301 shown in FIG. 8) of such measurements may allow real-timequantification of changes in concentration of anesthetic drugs in bloodduring anesthesia. In some embodiments, several multivariateclassification methods may be used, including partial-least square(PLS), principal component regression (PCR), linear discriminantanalysis (LDA), k-Nearest Neighbors (kNN), Naive Bayesian classifier(NBC), Support Vector Machine (SVM), Artificial Neural Networks (ANN),etc. With a linear approximation, the Propofol concentration (in g/mL,mol/mL, etc.) may be considered as the dependent variables (Y), and therest of the variables, for instance data matrices of differentmeasurement units are the independent variables (X). The purpose of amultivariate classification (e.g., multiple regressions) may be to finda solution that best predicts the ‘Y’ variable as a linear (ornon-linear) function of the ‘X’ variables.

For example, the general equation for the multiple regression may be:

$Y = {{b_{0} + {b_{1}x_{1}} + {\ldots\mspace{14mu} b_{k}x_{k}} + f} = {{b_{0} + {\sum\limits_{i = 1}^{k}{b_{i}x_{i}}} + f} = {b_{0} + f + {BX}}}}$where ‘Y’ is the response (for Propofol concentration), ‘x_(k)’ are thepredictors (e.g., data matrices of different measurement units), ‘b_(k)’are the regression coefficient to be determined, b₀′ is the offset and aconstant factor, and ‘f’ is the residual. If ‘X’ and ‘Y’ aremean-centered, then b₀=0. Thus, the above equation may be written inmatrix form: Y=Xb+f.

According to some embodiments, variety of spectral regions in differentmeasurement units (e.g., transmission and/or reflectance and/orFTIR-ATR) may be examined separately and/or in combination to obtainoptimal classification accuracy.

According to some embodiments, a measurement unit may further include atleast one of a display (e.g., a touchscreen displaying patient data), apower supply unit, a patient data unit (e.g., with oxygen saturation,blood pressure, and heart rate), an anesthetic drug monitor (ADM) clip,and an anesthesia degree analysis unit (e.g., collects in real time thepatient data and the ADM data and gives a new combined value (deep ofanesthesia value, DAV). In some embodiments, the display may include aCapnometer to display the capnogram, respiratory rate, and end-tidal CO₂(EtCO₂). In some embodiments, the display may include a pulse Oximeterto display the plethysmogram and oxygen saturation. The Capnometer andpulse Oximeter may operate in tandem to detect indicators of oversedation, such as low respiratory rate, apnea, and low oxygensaturation.

In some embodiments, the display may include an electrocardiogram todisplay the electrocardiogram and heart rate. In some embodiments, thedisplay may include anon-invasive blood pressure display withlast-measured systolic and diastolic blood pressure. In someembodiments, the display may include an ADM to assess the level ofsedation by measuring patient Propofol blood level. In some embodiments,the display may include a deep anesthesia value (DAV) to calculate thelevel of sedation after collecting all the patient data and Propofollevel in the blood.

FIG. 9 shows an example graph of detection of injected substance overtime, in accordance with an embodiment of the present invention. Thegraph in FIG. 9 was obtained by assembling a light sensor on a bloodvessel of a wrist of a patient while Propofol was injected intravenouslyby a target controlled injection (TCI) syringe pump. The ‘X’ axis is atime scale and the ‘Y’ axis is the relative absorption. Both injectiontiming and continuous measurement with SWIR sensor were carried out onthe same time scale. The data log provided by the syringe pumpdemonstrates time of injection 401 commencement and finish.

The graph shown in FIG. 9 may be obtained with a measurement unit 300 asshown in FIG. 8. As may be appreciated by one of ordinary skill in theart, after injection 401 of a drug (e.g., injecting 30 milligrams of apredetermined drug) into the bloodstream, a peak 402 in absorbance(e.g., a peak of about 50%) may be observed in less than a minute. Thegraph shows a typical response of the system at a given wavelength onPropofol injections. The injections are accompanied by a sharp increaseof the signal with subsequent trend. The amplitude of peaks 402 and theform of trend (or rate of change) depend on the concentration of theinjected Propofol.

FIG. 10 shows an example of a transmission measurement unit 500, inaccordance with an embodiment of the present invention. Transmissionmeasurement unit 500 may include an attachable body 505 (e.g., a clip,such as attachable segment 305 shown in FIG. 8) configured to attachonto an outer ear portion 62 of a patient. In some embodiments,attachable body 505 may have a pressure mechanism configured to controlpressure applied by the attachable body 505 (e.g., with elasticmaterial), for example a user may reduce the pressure if the patientexperiences pain or discomfort.

Transmission measurement unit 500 may further include, for instanceembedded within the attachable body 505, a processor 501, a light source502 and a light detector 503 coupled therebetween such that processor501 may analyze measurement data received at light detector 503 forlight transmitted through outer ear portion 62 from the light source502. In some embodiments, at least one of light source 502 and lightdetector 503 may be coupled to optical elements (e.g., lens, such asoptical elements 306 shown in FIG. 8).

In some embodiments, transmission measurement unit 500 may furtherinclude a communication module (e.g., for Bluetooth communication withan external device, such as communication module 308 in FIG. 8) and/or amotion sensor 504 embedded within the attachable body 505. In someembodiments, the attachable body 505 may include a contact portion 515(e.g., with elastic material) configured to contact the outer earportion 62 of the user, where light source 502 may be embedded withinthe contact portion 515.

FIGS. 11A-11C show a reflectance measurement unit 600, in accordancewith an embodiment of the present invention. FIG. 11A shows a top view,FIG. 11B shows a side view and FIG. 11C shows a cross-section of aperspective view. Reflectance measurement unit 600 may be removablyattached (e.g., with a bio-adhesive strip) onto a body portion of thepatient where a blood vessel is visible through the skin such as the armor the skull for infants to allow optical reflectance measurements ofpredetermined substances (e.g., Propofol) in the blood stream.

Reflectance measurement unit 600 may include a hollow base 601 (e.g.,disc shaped) removably attachable to the patient or to patient's tissue(e.g., with a bio-adhesive strip or other suitable attachment device),and coupled to a clipping element 602 and a transceiver portion 603. Insome embodiments, base 601 may be an adhesive strip. In someembodiments, clipping element 602 may include optically transparentmaterial such that light may pass therethrough, for instance light beamsmay pass into a hollow center 604 of base 601 to penetrate skin tissue22 of the patient. In some embodiments, the user may view skin tissue 22through hollow center 604 and thereby position reflectance measurementunit 600 over a blood vessel. In some embodiments, transceiver portion603 may include at least one indicator 609 configured to indicate to theuser at least one of reflectance measurement unit 600 operation andpositioning over a blood vessel (e.g., detecting a change in readingwhen positioned over a blood vessel).

In some embodiments, clipping element 602 may be manually moved (e.g. inat least one direction) to allow the user to view skin tissue underneath(e.g., via hollow center 604) and thereby position the reflectancemeasurement unit 600 over a blood vessel of the patient. In someembodiments, clipping element 602 may be manually rotated 611 around thehollow center 604 and/or clipping element 602 may be manually movedalong axis ‘X’ along arms 607 of the clipping element 602. In someembodiments, arms 607 of the clipping element 602 (e.g., includingelastic material) may be gripped by a user to release/attach clippingelement 602 to base 601 using abutting elements 608. For example, theuser may push arms 607 towards transceiver portion 603 and therebyrelease clipping element 602 from base 601 so as to allow relativemovement (e.g., manual rotation of clipping element 602 relative to base601).

In some embodiments, transceiver portion 603 may be configured to emitlight beams towards the skin of the patient with at least one lightsource 605 (e.g., such as light source 302 in FIG. 8) and detect lightreflected back with at least one light sensor 606 (e.g., such as lightsensor 303 in FIG. 8). In some embodiments, transceiver portion 603 mayfurther include a processor 610 configured to operate the at least onelight source 605 and at least one light sensor 606 and analyze thereceived data to determine concentration of substances (e.g., Propofol)in the blood stream. It should be noted that while at least one lightsource 605 and at least one light sensor 606 are schematically shown ata distance from the plane of base 601, in some embodiments at least onelight source 605 and at least one light sensor 606 may be at the planeof base 601 so as to allow contact of skin tissue with base 601, atleast one light source 605 and at least one light sensor 606.

In some embodiments, transceiver portion 603 may further include atleast one of motion sensor (e.g., such as motion sensor 304 in FIG. 8)and a communication module (e.g., via Bluetooth, such as communicationmodule 308 in FIG. 8) so as to communicate with an external device.

According to some embodiments, transceiver portion 603 may communicate(via the communication module) with the transmission measurement unit500 (e.g., via Bluetooth) to compare and/or analyze combinedmeasurements, where measurements by transceiver portion 603 andtransmission measurement unit 500 may be carried out simultaneously.

In some embodiments, transceiver portion 603 may further include avisible light switch (e.g., manually operated by the user) such thatduring illumination of visible light (e.g., wavelengths of 400-900 nm),signals reflected from the skin may be read with visible light. In caseof minimal reflectance detected by the at least one light sensor 606,for instance due to maximal absorbance, positioning of transceiverportion 603 over a blood vessel may be determined. Once positioning oftransceiver portion 603 over a blood vessel is determined, measurementsin other wavelengths (e.g., IR, SWIR, etc.) without the visible lightmay be carried out in order to determine concentration of substances inblood.

FIGS. 12A-12B show a flowchart for a method of noninvasive analysis oftissue, in accordance with an embodiment of the present invention. Insome embodiments, a surface of the tissue may be irradiated 701 (e.g.,with at least one source of infrared radiation) with infrared radiationin a first spectral band that is strongly absorbed by water, and withinfrared radiation in a second spectral band such that an interaction ofthe radiation in both spectral bands with a component of the tissueother than water may be substantially identical. In some embodiments, anintensity of the radiation may be measured 702 (e.g., with at least oneradiation detector) that emerges from the tissue in each of the spectralbands.

Change in at least one of shape and intensity of signals received by theat least one radiation detector may be determined 703 (e.g., by aprocessor). A relative absorption by the tissue of radiation may becalculated 704 (e.g., by the processor) in one of the first and secondspectral bands relative to absorption by the tissue of radiation in theother of the first and second spectral bands. Concentration of apredetermined substance may be determined 705 (e.g., by a processor) inaccordance with the calculated relative absorption and in accordancewith determined change in the received signal. The interaction of theradiation may include at least one of absorption and scattering. Otheror different operations may be performed.

Unless explicitly stated, the method embodiments described herein arenot constrained to a particular order in time or chronological sequence.Additionally, some of the described method elements can be skipped, orthey can be repeated, during a sequence of operations of a method.

Various embodiments have been presented. Each of these embodiments mayof course include features from other embodiments presented, andembodiments not specifically described may include various featuresdescribed herein.

The invention claimed is:
 1. A method of noninvasive analysis of tissue,the method comprising: irradiating, with at least one source of infraredradiation, a surface of the tissue with infrared radiation; measuring,with a plurality of radiation detectors at different lateral distancesfrom the at least one source of infrared radiation, an intensity of theradiation that emerges from the tissue by each of the detectors;determining, by a processor, a change in at least one of shape andintensity of signals received by the radiation detectors; anddetermining, by the processor, concentration of a predeterminedmedication, in accordance with the determined change in the at least oneof shape and intensity of signals and in accordance with the distancebetween the corresponding radiation detector and the at least one sourceof infrared radiation, wherein the infrared radiation is in thewavelength range of at least one of: 500 nm to 900 nm, 1000 nm to 1350nm and 1500 nm to 2100 nm.
 2. The method of claim 1, wherein thepredetermined medication is Propofol.
 3. The method of claim 1,comprising irradiating with at least one of short wave infrared (SWIR)radiation and near infrared (NIR) radiation.
 4. The method of claim 1,wherein measuring the intensity comprises measuring the intensity of theradiation that is at least one of transmitted across the tissue andreflected by the tissue.
 5. The method of claim 4, wherein themeasurements are carried out at two different portions of tissuesimultaneously.
 6. The method of claim 1, wherein the measurements withthe radiation detector are carried out with at least one of Ramanspectroscopy and attenuated total reflection (ATR) spectroscopy.
 7. Asystem for noninvasive analysis of tissue, the system comprising: atleast one source of infrared radiation configured to irradiate thetissue; a plurality of radiation detectors, at different lateraldistances from the at least one source of infrared radiation, to measurean intensity of radiation by each of the detectors; and a processor thatis configured to calculate a change in at least one of shape andintensity of signals received by the radiation detectors and determineconcentration of Propofol in accordance with the change in the at leastone of shape and intensity of signals and in accordance with thedistance between the corresponding radiation detector and the at leastone source of infrared radiation, wherein infrared radiation is in thewavelength range of at least one of: 500 nm to 900 nm, 1000 nm to 1350nm and 1500 nm to 2100 nm.
 8. The system of claim 7, wherein said atleast one radiation detector is configured to measure the intensity ofthe radiation that emerges from a surface of the tissue that isirradiated by said at least one radiation source.
 9. The system of claim7, wherein said at least one radiation detector is configured to measurethe radiation that emerges from a surface of the tissue that issubstantially opposite a surface of the tissue that is irradiated bysaid at least one radiation source.
 10. The system of claim 7, furthercomprising a light source for visible light configured to allowidentification of a blood vessel.
 11. The system of claim 7, furthercomprising at least one indicator coupled to the processor andconfigured to indicate measurements by the at least one radiationdetector.
 12. The system of claim 7, wherein said at least one radiationsource comprises two radiation sources, one of the sources beingconfigured to emit radiation in a first spectral band and the otherbeing configured to emit radiation in a second spectral band.
 13. Thesystem of claim 7, wherein said at least one radiation detectorcomprises two radiation detectors, one of the detectors being configuredto measure an intensity of radiation in a first spectral band and theother being configured to measure an intensity of radiation in a secondspectral band.
 14. The system of claim 7, comprising a dispersiveelement to separate spectral components of the infrared radiation and amicro-mirror array, the micro-mirror array configured to direct aselected spectral component of the infrared radiation to the tissue orto said at least one radiation detector.
 15. The system of claim 7,wherein the at least one radiation detector is configured to measure theintensity of the radiation that is at least one of: transmitted acrossthe tissue and reflected by the tissue.
 16. A device for noninvasiveanalysis of tissue, the device comprising: a base, configured to beremovably attachable to skin tissue; a clipping element, removablyattachable to the base; a transceiver portion, coupled to the clippingelement and comprising: at least one source of infrared radiationconfigured to irradiate the tissue; a plurality of radiation detectorsat different lateral distances from the at least one source of infraredradiation to measure an intensity of radiation that emerges from thetissue; and a processor that is configured to calculate a change in atleast one of shape and intensity of signals received by the radiationdetectors and determine concentration of Propofol in accordance with thechange in the at least one of shape and intensity of signals and inaccordance with the distance between the corresponding radiationdetector and the at least one source of infrared radiation, wherein theclipping element is configured to move the transceiver portion relativeto the base in at least one direction, wherein the infrared radiation isin the wavelength range of at least one of: 500 nm to 900 nm, 1000 nm to1350 nm and 1500 nm to 2100 nm.